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What are host cellular factors?

What are host cellular factors?


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With respect to this paper:

Global Analysis of Host-Pathogen Interactions that Regulate Early-Stage HIV-1 Replication

What does the term "host cellular factors" mean??


Generally spoken, "host cellular factors" are proteins, receptors etc. of the host cell. In this case, they are important for the HIV infection. The authors write:

Recently, a genome-wide siRNA analysis revealed over 250 host cellular factors that influence HIV-1 infection.

This means gene silencing techniques where used to identify the host cellular factors which are important for the infection, you can find these results here: "Identification of host proteins required for HIV infection through a functional genomic screen." The overall goal is to identify proteins which are important for the function and infection of HIV to understand the interaction between virus and host cell better.


Cell biology of Candida albicans–host interactions

The cell biology of Candida albicans is adapted both for life as a commensal and as a pathogen.

C. albicans can either downregulate or upregulate virulence properties in the human host.

This fungus modulates the activity of phagocytes to enable its own survival.

Candida is metabolically flexible enabling it to survive in multiple niches in the host.

Candida albicans is a commensal coloniser of most people and a pathogen of the immunocompromised or patients in which barriers that prevent dissemination have been disrupted. Both the commensal and pathogenic states involve regulation and adaptation to the host microenvironment. The pathogenic potential can be downregulated to sustain commensalism or upregulated to damage host tissue and avoid and subvert immune surveillance. In either case it seems as though the cell biology of this fungus has evolved to enable the establishment of different types of relationships with the human host. Here we summarise latest advances in the analysis of mechanisms that enable C. albicans to occupy different body sites whilst avoiding being eliminated by the sentinel activities of the human immune system.


DNA Excision Repair Assays

F Host Cell Reactivation

Host cell reactivation measures the in vivo restoration of biological activity to in vitro-damaged DNA. The ability of UV-damaged viruses to replicate in infected cells hinges on the genetic makeup of the host cells. The use of damaged phage or plasmid DNA provides certain advantages over direct treatment of cells with a DNA-damaging agent in studying the cellular DNA repair mechanism. In this assay the physiology of the cell is not perturbed by the DNA-damaging treatment and, as a consequence, the fate of the transfecting DNA is solely dependent on the capacity of the host cell to process DNA damage. Most viruses use host cell proteins to repair and replicate. Taking advantage of this, a repair assay was designed to use the ability of UV-damaged viruses or plasmids to replicate in host cells as an indicator of the host repair capacity. This forms the basis for the host replication-dependent Host Cell Reactivation assay ( 8388 ). More recently, the chloramphenicol acetyltransferase (CAT) assay, originally developed to study transcriptional control in mammalian cells, was adapted to study DNA repair and mutagenesis ( 89 ). Instead of viruses, a UV-damaged vector DNA carrying a gene with a readily detectable phenotype (e.g., chloramphenicol acetyltransferase) is used to transfect host cells. In the absence of host repair, UV lesions block transcription ( 90 ), leading to reduced production of CAT and hence a reduced level of CAT activity, and vice versa. Alternatively, with an appropriate plasmid/host system, after a round of replication the plasmid is isolated from the mammalian cells and transfected into indicator bacterial cells to detect mutations ( 91 ).


Host cell factors in filovirus entry: novel players, new insights

Filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. The cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. The viral glycoprotein (GP) mediates filovirus entry into host cells. Recent studies revealed important insights into the host cell molecules engaged by GP for cellular entry. The binding of GP to cellular lectins was found to concentrate virions onto susceptible cells and might contribute to the early and sustained infection of macrophages and dendritic cells, important viral targets. Tyrosine kinase receptors were shown to promote macropinocytic uptake of filoviruses into a subset of susceptible cells without binding to GP, while interactions between GP and human T cell Ig mucin 1 (TIM-1) might contribute to filovirus infection of mucosal epithelial cells. Moreover, GP engagement of the cholesterol transporter Niemann-Pick C1 was demonstrated to be essential for GP-mediated fusion of the viral envelope with a host cell membrane. Finally, mutagenic and structural analyses defined GP domains which interact with these host cell factors. Here, we will review the recent progress in elucidating the molecular interactions underlying filovirus entry and discuss their implications for our understanding of the viral cell tropism.

Figures

Domain organization of selected viral…

Domain organization of selected viral class I membrane fusion proteins. Viral class I…

Host cell surface proteins involved…

Host cell surface proteins involved in filovirus uptake. Cellular lectins bind glycans present…

Infectious entry of filoviruses into…

Infectious entry of filoviruses into target cells. After interaction between GP 1,2 and…


A Nonhospitable Host: Targeting Cellular Factors as an Antiviral Strategy for Respiratory Viruses

Respiratory viral diseases pose a frequent and potentially severe threat to humans, representing a significant cause of pneumonia (1). They affect millions around the globe, incurring a notably high mortality rate and producing an important negative impact on health (2, 3). Respiratory syncytial virus (RSV) can lead to a severe lower respiratory tract infection and is the leading cause of hospitalization and mortality in infants and young children (3–5). It also affects adults, increasing the risk of complications and death among the elderly (6–8). Because the treatment and prevention options for RSV are currently limited (9, 10), the development of novel pharmacological agents is of great interest.

Cardiac glycosides are steroidal compounds that are used clinically for the treatment of cardiac diseases. Their mechanism of action involves the binding and inhibition of, or interference with, the Na,K-ATPase that controls Na + , K + , and Ca 2+ ion flow in muscle and excitable cells (11). Cardiac glycosides not only impair ionic transport of Na + and K + across the membrane but can also activate complex intracellular signaling pathways that are essential for many biological processes (12, 13). A deeper understanding of the cellular changes induced by cardiac glycosides has widened their therapeutic potential. For example, cardiac glycosides have been studied for the last decade as antineoplastic drugs (14–16). Moreover, increasing scientific evidence suggests that cardiac glycosides have antiviral effects against a wide array of both RNA and DNA viruses (17). The antiviral properties of cardiac glycosides are a very promising feature, as targeting cellular processes rather than viral components can minimize the development of resistance, an important problem in antimicrobial therapy.

In this issue of the Journal, Norris and colleagues (pp. 733–744) report that the cardiac glycosides digoxin and digitoxin produced robust inhibition of RSV replication in vitro (18). These results are consistent with a study by Cui and colleagues, in which another cardiac glycoside, ouabain, also suppressed RSV replication by plaque assay (19). To determine whether the inhibitory effect of cardiac glycosides on RSV replication was due to decreased Na,K-ATPase activity and consequent changes in the intracellular concentrations of Na + and K + , the authors monitored RSV replication under conditions in which they could manipulate the concentrations of Na + and K + by either changing the extracellular ionic conditions or using ionophoric drugs. Their results suggest that modulation of both Na + and K + concentrations is involved in the antiviral effect.

Although these results open the door to new therapeutic options, the analysis has several flaws. First, the authors did not measure the actual ion concentrations achieved in the different experimental conditions, nor did they determine the mechanism by which the intracellular ion perturbation exerted antiviral effects. Moreover, changes in intracellular Ca 2+ and the relevance of calcium homeostasis in the anti-RSV effect were not addressed. A rise in the intracellular Ca 2+ concentration is a common effect of Na,K-ATPase inhibition, due to a decrease in Na + /Ca 2+ exchange (20, 21). Because many enzymatic and signaling processes depend on intracellular Ca 2+ , the intracellular concentration of Ca 2+ could play a notable role in the inhibition of RSV replication and should be taken into account.

Norris and colleagues’s elegant experiments show that cardiac glycosides and the consequent intracellular ionic changes affect an early but postentry step in the viral life cycle, which is consistent with previous reports for RNA and DNA viruses (17). However, as the authors point out, a consequence of using drugs that disrupt host cellular mechanisms is the associated cytotoxicity. Indeed, there was a narrow difference between the beneficial viral inhibitory effects and cytotoxicity of cardiac glycosides when compared with ribavirin. This finding warrants further research using in vivo models to demonstrate the efficacy of disrupting intracellular ion homeostasis as a treatment for RSV infection.

Unfortunately, the clinical relevance of cardiac glycosides and ionophoric compounds for treatment of human diseases is dampened by the potential health risks. The side effects of digoxin are well known and include mild gastrointestinal and neurological symptoms. Furthermore, cardiac glycosides can cause serious cardiovascular disorders, such as atrioventricular block and severe supraventricular and ventricular arrhythmias, leading to an increased risk of cardiovascular death in patients with atrial fibrillation (22, 23). Taking these undesirable effects into consideration, the likelihood of achieving direct clinical application of the antiviral strategies described in this work is slim nevertheless, an important message of this research is the susceptibility of RSV to changes in the intracellular environment, and particularly to disruption of ion homeostasis. These results warrant future research to identify novel, efficient, and safe anti-RSV therapeutics.

The study by Norris and colleagues emphasizes an important therapeutic approach against viruses: the targeting of host factors to prevent the development of resistance, which is an especially problematic occurrence in RNA viruses such as RSV due to high rates of mutation. The discovery of novel, specific, and broad-spectrum antivirals is an urgent necessity to fight respiratory viruses. The current study contributes to this goal by exploring a promising therapeutic mechanism.


Host-Parasite Relationship (With Diagram)

Parasitism is an association or a situation in which two organisms of different taxonomic posi­tions live together where one enjoys all sorts of benefits (like derivation of nourishment, repro­duction etc. which are basic requirements for exis­tence) at the expense of the other. The benefited organism is called the parasite and the organism harbouring the parasite is called the host.

Hosts are not hospitable to parasites. Instead they consider parasites as foreign bodies and want to exterminate or overpower them by operating various devices like: producing antibodies, increased peristalsis, diarrhoea, mucus secretion, encystation by host tissues etc. Parasites to avoid host’s reaction for existence develop many specialities like increased fecun­dity, polyembryony, safe-habitat, production of special enzymes, a good deal of transmission etc.

Due to close contact/intimate association, the responsive reactions and resis­tance displayed by a host to its parasite and the protective devices adopted by a parasite in response to its host’s reactions in order to establish them in their respective environments are called host-parasite-interactions. Parasitism is a very broad term and different types of parasites are recognised on different basis.

In the course of their life cycle, parasite may become associated with more than one host. In many cases the life cycle is characterised by numerous very rigid requirements. Whenever a parasite is able to live and repro­duce within a host—the result is an elaborate host- parasite interactions.

Host Specificity of Parasites:

In mature condition a given parasite is quite often found in limited number of hosts. In extreme condition, distribution of a parasite may be restricted to a single host—mono-specific parasite. Even when poly-specific the different hosts are phylogenetically related. This host specificity is a function of physiological specialization and evolutionary age.

It is broadly divided into two parts:

(a) Ecological specificity:

The parasites are capable of making room in a foreign host but normally never reach another host due to ecological barriers. Such parasites are able to develop in more host-species under labora­tory conditions than in nature.

(b) Physiological specificity:

The parasites are physiologically incapable of surviving and reproducing in a foreign host, e.g., Taenia solium in dog survives but never achieves reproductive ability. If the parasites find the conditions suitable for their development—then it is said to be compa­tible with that of the host. If not, it is said to be incompatible.

Host and Parasite: A Mutual Relation:

In the course of time a mutual adjustment or relation or tolerance frequently develops between the two which permits them to live together as a sort of compound organization without very serious effect or damage to either.

The virulant types, however, try to eradicate the hosts. But it is essential to keep the host alive and not to kill it by causing a high degree of pathogenecity. By killing the host it will ultimately lead to death of itself also. Accordingly Natural Selection leads to the elimination of most virulent species and maintains the less virulant ones.

Effects of Parasites on Hosts:

The effects of parasitism on the hosts are intimately asso­ciated to the effect of host on the parasites. These effects depend on several factors, such as—age, diet, genetic factors, susceptibility of the hosts, the size, number and virulence of the parasites, their mortality, migration, and method of feeding.

A. Destruction of Host’s Tissues:

Time and degree of damage vary greatly:

i. Some parasites injure the host’s tissue dur­ing the process of entry, e.g. hookworms like Ancylostoma duodenale, whose infective larvae inflict extensive damage to cells and underlying connective tissue while pene­trating the host’s skin.

ii. Some inflict tissue damage after they have entered, e.g., larvae of Ascaris lumbricoides while passing through lungs of human host cause physical damage to lung-tissue, leading to pneumonia.

iii. Others induce to histopathology changes by eliciting cellular immunologic response to their presence, e.g. Entamoeba histolytica actively lyses the epithelial cells lining the host’s large intestine and liver causing large ulcerations by the action of secreted enzymes.

2. Types of cell damage:

i. Parenchymatous or albuminous degene­rative cells become swollen and packed with albuminous or fatty granules and pale cytoplasm. This type of damage is characteristic of liver, cardiac muscle and kidney cells.

ii. Fatty degeneration cells are filled with an abnormal amount of fat deposits, e.g. liver cells.

iii. Necrosis means any type of persistent cell degeneration which finally die, e.g. as the result of encystment of Trichinella spiralis in mammalian skeletal muscles necrosis of surrounding tissue is followed by calci­fication.

i. Refers to an increased rate of cell division resulting from an increased level of cell metabolism.

ii. Leads to a greater total number of cells but not in their sizes.

iii. This commonly follows an inflammation and is the consequence of an excessive level of tissue repair.

iv. For example—thickening of bile duct in presence of Fasciola sp. is the result of hyperplasia.

i. Refers to an increase in cell size.

ii. Commonly associated with intracellular parasites.

iii. For example in Erythrocytic phase of Plasmodium vivax, the parasitized RBC’s are commonly enlarged. Spermatogonial cells of Polymnia nebulosum (an Annelid) when parasitized with Caryotropha mesnili (a Protozoan), are enlarged.

i. Refers to the changing of one type of tissue into another without the intervention of embryonic tissue.

ii. The encapsulating epithelial cells and fibroblasts of the fluke, Paragonimus westermani in human lungs are transformation of certain other type of cells in the lungs.

i. This is the growth of cells in a tissue to form a new structure, e.g., a tumour.

ii. Neoplastic tumour is not inflammatory.

iii. This is not required for the repair of organs.

iv. It does not conform to a normal growth pattern.

v. It may be benign or malignant.

Eimeria sp. causes tumor in rabbit liver, Schistoma mansoni in human intestine and liver, Echinococcus granulosus in human lungs etc.

B. Competition for host’s nutrients:

i. Endoparasites with a great density causes nutritional deficiency in host by absorbing sugars, vitamins, amino-acids etc.

ii. Mal-nourished hosts are more proned to disease and infection.

Diphyllobothrium latum (a fish tapeworm) in human causes anaemia by absorbing profuse Vitamin B12 (as much as 10 to 50 times more than do other tape-worms). Vitamin B12 plays an impor­tant role in blood formation, thus its uptake by D. latum results in anaemia.

C. Utilisation of host’s non-nutritional mate­rials:

Parasites in some cases also feed on host- substances, other than stored or recently acquired nutrients. Ectoparasites and endoparasites feed on host’s blood, 500 human hookworms can cause a loss of about 250 ml blood/day, leading to anaemia.

Mechanical interferences:

Mechanical inter­ferences by parasite cause injuries to hosts, e.g. elephantiasis or filariasis in humans is caused by Wuchereria bancrofti. Increased number of those adult worms in lymph vessels coupled with aggregation of connective tissue may result in complete blockage of lymph flow.

Excess fluid behind the blockage seeps through the walls of lymph ducts into the surrounding tissues, causing edema and ultimately with scar tissues—the elephantiasis of limbs, breasts, scrotum etc.

Effects of toxins, poisons and secretions:

Specific poisons or toxins egested, secreted or excreted by parasites cause irritation and damage to hosts, e.g.

i. Antienzymes produced by intestinal para­sites counteract host’s digestion.

ii. Allergin, a toxin as the body fluid of nematodes—Parascaris equorum and other ascarids, irritates the host’s cornea and nasopharyngeal mucous membrane.

iii. Toxin of pathogenic Entamoeba histolytica produces toxic symptoms in parasitized mammalian hosts and creates ulcerations within the large gut of man.

iv. Schistosome cercarial dermatitis is the result of an allergin reaction against an irritating parasitic secretion from the fluke.

v. Haemozoin pigment produced by tropho­zoites of P. vivax exert toxic effect in infec­ted persons and the patients suffer from periodic effect of high fever with chilliness and shivering.

Other parasite-induced alterations:

(a) Sex reversals:

Gonads of parasitized hosts may change, leading to sex reversals e.g. crab when parasitized by Sacculina (a crustacean) display sex reversals. Parasitized male crab acquired secondary female characteristics like broad abdomen, appendages modified to grasp eggs, chelae become smaller, testes with testicular cells at various stages of degeneration.

Parasite-removed male develops into hermaphrodite by regene­ration of rest testicular cells. Parasitized female crab shows ovarian dege­neration but does not show hermaphroditism on removal of parasite, as ovarian tissue cannot regenerate.

(b) Parasitic castration:

i. It refers to destruction of host’s gonadal tissues by a parasite.

ii. Reduces egg and/sperm production in host’s body or becomes sterile.

iii. The mudflat snail—Ilyanassa obsoleta are directly castrated by the trematode— Zoogonus lasius. Sporocysts of Z. lasius secrete a molecule that causes the destruc­tion of host reproductive cells as well as inhibits same to genesis.

The freshwater snail, Lymnaea stagnalis is indirectly castrated by larvae (Sporocysts) of Trichobilharzia ocellata (a trematode). These larvae do not possess mouth and thus destroy the gonadal tissue by chemical means.

(c) Enhanced growth of host:

An interesting aspect of parasite induced change in hosts is responsible for enhanced growth e.g.

i. Workers of the ant, Pheidole commutula become much larger when parasitized by the nematode, Mermis sp.

ii. Fresh water snail, Lymnaea ariculata infected with trematode larvae is larger than un­infected ones.

iii. Mice infected with larvae of Spirometra mansonoides (a tapeworm) grows faster than non-parasitized one.

iv. Rats when parasitized by Trypanosoma lewise increase their weight more rapidly than non-parasitized one.

The enhanced growth of the host is due to stimulation of growth-promoting molecules secreted by the parasites.

In immuno-parasitology, the animal is the host and the parasite is either self (by molecular memory) or non-self (foreign).

When a host recognizes the parasite as non-self, it generally reacts against the invader in two ways:

1. Cellular (or cell mediated) reactions:

Where specialised cells become mobilised to arrest and eventually destroy the parasite as usual.

Where specialised molecules in circulatory system (antibodies/ immunoglobulin’s in case of vertebrates) interact with the parasite, usually resulting in its immobilization and destruction.

Internal defense mechanisms:

The internal defense mechanisms of animals, both inverte­brates and vertebrates, are of two types:

Theoretically each of them again can be of two types—cellular and humoral.

Invertebrate immunity:

I. Innate internal defense mechanism:

These includes the following chief categories:

When a foreign parasite (small enough to be phagocytosed) invades into an invertebrate host, it is usually phagocytosed by the host’s leucocytes, primarily the granu­locytes.

Phagocytosis consists of three phases:

i. Attraction of phagocytes to the non-self material, commonly by chaemo-taxis.

ii. Attachment of foreign material to the sur­face of the phagocyte, usually involving a specific chemical binding site.

iii. Internalization of the foreign substance i.e. engulfment by the phagocyte.

Fate of phagocytosed parasites:

i. May be degraded intracellularly.

ii. May be transported by phagocytes across epithelial borders to the exterior.

iii. May remain undamaged within the phagocytes and some may even multiply within host cells.

1. Parasites, that are too large to be phago­cytosed, are encapsulated as invading non-self mass enveloped by cells and/or fibres of host origin, as found in insect and molluscan hosts.

2. Encapsulation consists of:

(i) First leucocytosis (increase in number of leucocytes)

(ii) Migration—many of these cells migrate by the process of chaemo-tactic movement towards the parasite and form a capsule of discrete cells around it, as found in insects and in other cases (i.e., in molluscs).

Host cells synthesize fibrous material which becomes deposited inter-cellularly and con­centrically in layers around the parasite.

3. Encapsulation of Tetragonocephalum (a tape­worm) in the American oyster, Crassostrea virginica.

Fate of encapsulated parasite:

Destroyed and disintegrated parasite’s tissues are phagocytosed by host’s granulocytes.

(c) Nacrezation (i.e. pearl formation):

1. Nacrezation is another type of cellular defense mechanism, known in molluscs.

2. As certain helminth parasites, e.g., Meiogymnophallus minutus (a trematode) occurs between the inner surface of the shell (nacreous layer) and the mantle of marine bivalves. Now the mantle is stimu­lated to secrete nacre that becomes deposited around the parasite. In so doing, a pearl is formed and the enclosed parasite is killed.

1. The process involves deposition of the black-brown pigment, melanin around the invading parasite.

2. Melanization is chemically the result of enzymatic oxidation of polyphenol by tyrosinase.

3. This is detrimental to the parasite and may lead to its death by interfering with such vital activities like hatching, moulting or feeding.

4. Melanization of the nematode, Heterotylenchus autumnalis in haemocoel of larval house-fly—Musca domestica.

These fall into two categories:

(a) Innate humoral factors:

i. Those are directly parasitocidal, e.g. seve­ral marine molluscan species contain a constituent in their tissue extract that is lethal to Cercariae of the trematode, Himasthla quissetensis.

ii. Those that enhance cellular reactions, e.g., naturally occurring agglutinins or lectins. These glycoprotein molecules enhance phagocytosis of the non-self-material.

(b) Acquired humoral factors:

These are also of two types:

When challenged with non-self-parasites, some invertebrate’s granulocytes (haemocytes) hypersynthe size certain lysosomal enzymes and sub­sequently release them into some parasites. When they come in contact with elevated enzymes are killed either directly or indi­rectly whereas the parasite’s body surface by action of lysosomal enzyme undergoes chemical alteration and thus is recognized as non-self-material and consequently get attacked by host’s haemocytes.

ii. Antimicrobial molecules:

When chal­lenged with micro-organisms, some insects synthesize antimicrobial mole­cules which are quite different from verte­brate antibody but kill the microorga­nisms, e.g. the synthesis of two small basic proteins (PgA and PgB) by the moth, Hyalophora cearopia when challenged with E. coli and these proteins kill the bacterium.

Immunity refers to resistance against disease caused by a foreign agent. This is based on anti­gen-antibody interaction. In vertebrates this reac­tion is very specific. Antigen is the only foreign substance (Proteins, glycoproteins, nucleoproteins etc.) which on introduction induces the synthesis of antibody under some appropriate conditions. All zoo-parasites theoretically contain multiple anti­gens.

These are chiefly of two types:

i. Somatic antigens molecules comprising some of parasites.

ii. Metabolic antigen molecules are associa­ted with secretion and excretion, e.g., moul­ting fluid of nematode is highly antigenic.

Antibody—Refers to proteins synthesized by host tissue in response to the administration of an antigen and which specifically react with that anti­gen to immobilize and destroy it.

Mechanism of antigen-antibody interactions:

i. Antigens on introduction are able to bind with specific cell surface receptor of lym­phocytes (both B and T-lymphocytes).

ii. Host lymphocytes are now stimulated to proliferate and differentiate.

iii. As a consequence, clones of progeny lym­phocytes are formed.

iv. In the process of proliferation, some pro­geny differentiate into effector cells (the functional end products of the immune response). Plasma cells are B-lymphocyte effector cells that secrete antibodies. Killer T-cells are such T-lymphocyte effector cells that eliminate foreign cells simply by con­tact.

v. As soon as immunoglobulin’s are pro­duced, immunogens are coated with such antibodies and are rapidly destructed and / or phagocytosed.

The parasites try to establish itself within the host while the latter tries to destroy it which results in dynamic state of equilibrium. The reaction of the host in the presence of a parasite is termed as resis­tance. If resistance is sufficiently high to prevent parasite reproduction, it is known as absolute resistance and if parasite is able to overcome it and still reproducing it is called partial resistance.

(a) In case of larger parasites there is consider­able damage to host tissues where histamin is released, macrophages are attracted and a primary stage of inflammation is set up.

(b) In the second stage, the cells of the lymphoid macrophage system elaborate antibodies. The immunoglobulin’s appears in various molecular forms differing in properties and actions. The macroglobulin’s (IgM) is the first to appear in an infected animal. This is follo­wed by the appearance of gamma-globulin and alpha-globulin (IgA). The properties and number of antibodies vary from individual to individual parasitic infections.

(c) Interferons also play an important role in the immunity reaction of the host. These are known to operate in malaria and other viral reactions by rendering the host cells unfit for habitation by intercellular parasites.

Categories of antigen-antibody interactions:

These are of three types:

1. Primary interaction:

Refers to the basic event during which the antigen is bound to and/or more available sites on the antibody molecule.

2. Secondary interactions:

Include agglutina­tion, precipitation, complement-dependent reaction, neutralisation, immobilisation etc.

i. Agglutination reaction:

Antibodies (agglu­tinins) clump microbes representing anti­gens and visible conglomerates are formed. This is referred to as agglutination reaction.

ii. Lysin and lysis reaction:

Lysin (antibodies) dissolves or lyses antigens. The reaction occurs in the presence of complement, a substance in normal serum representing a system of enzymes. Complement is sensi­tive to heat, chemical substances, ultravio­let rays, long-term storage etc.

iii. Complement-dependent reaction:

In the first phase of this reaction mutual adsorp­tion of antigen-antibody takes place and precipitation occurs. In the second phase of reaction the fixation of complement by antigen-antibody occurs which is used for detecting many of the parasitological infections.

iv. Precipitin reaction:

Precipitin is the anti­body that brings about the formation of a minute deposit (precipitation) when inter­acted with specific antigen (precipitino­gen). While in agglutination the entire microbial bodies act as antigen, in preci­pitin the antigen will be the results of breakdown of microbial bodies or their products. This precipitin reaction is used for detecting infections like plague, anthrax, tularaemia etc.

Refers to the engulfment of non-self-material by host cell like macro­phages. In vertebrates, this is introduced through the action of antigen, antibody and complement.

This occurs in two ways:

(1) Accumulation of leucocytes through complement sequence and

(2) Certain anti­bodies called opsonins become coated on to the foreign materials and they enhance phagocytosis.

Opsonins are antibodies occurring in normal as well as in immune sera which inhibit microbes making them more amenable to phagocytosis.

3. Tertiary interaction:

Refers to in vivo expres­sions of antigen-antibody reactions. At times these may be of survival value to the host, but at other times they may lead’ to a disease through immunologic injury.

Immunity to parasites:

Vertebrate hosts always develop some degree of acquired immu­nity in the presence of parasites.

This is usually of two types:

i. Concomitant immunity:

Where immu­nity, either complete or partial, may be maintained only while the parasites are present.

Where immunity per­sists long after the complete disappea­rance of the parasites.

Protozoan blood parasites:

i. Cattle infected with certain species of Babesia shows premonition.

ii. While cattle, long after Theileria parva has disappeared, shows sterile immunity.

iii. For malaria-causing parasites—Premoni­tion usually occurs in case of avian- infecting species of Plasmodium while sterile immunity can be produced with the rodent malaria causing agents P. berghei and P. vinckei (Fig. 16.3).

iv. Certain breeds of cattle develop partial immunity against Trypanosoma.

Protozoan tissue parasites:

(a) Antibodies are produced by host cells when they come in contact with antigens of para­sites. Thus,

i. When Entamoeba histolytica resides in host’s intestinal lumina, no detectable anti­body occurs, but when the Amoeba invades the mucosa and other tissues, antibodies are evident.

ii. For Leishmania tropica, if the sores pro­duced by this parasite are allowed to heal spontaneously, the host becomes totally immuned to reinfection.

iii. Immunity to Toxoplasma gondii is evident in adult humans who show the antibodies, while congenital infection with T. gondii leads usually to death and those who sur­vive, show a hydrocephalus condition. Immunity can control the intracellular stages only if the macrophage becomes successfully activated, which requires pro­duction of cytokines by T-cells.

iv. The trophozoites of gregarines (Gregarina sp) exhibit an eerie gliding movement. Various theories have been put forward. Similar movement has been noticed for the trophozoites of Plasmodium and Eimeria. There is little evidence of an effec­tive immunity against merozoites of Eimeria sp and Gregarina sp.

Experimental studies have shown that immunity can directly affect intracellular developmental stages in both initial and subsequent infec­tions. This immunity relies on the produc­tion of cytokine interferon, presumably activating an intracellular defence mecha­nism that is capable of preventing sporozoite and merozoite development.

(b) Special manifestations are shown by Trypano­soma. Parasites may change their surface anti­gens during their life cycle in vertebrate hosts. Continuous variation in major surface anti­gens is also shown by African trypanosomes. In such case, infected individual show waves of blood parasites. Each wave comprises of parasites expressing a surface antigen that is different from the previous wave.

Thus, by the time the host produces antibodies against the parasites, an antigenically new organism has grown out. Such continuous antigenic varia­tions make it difficult to effectively vaccinate the infected individuals (Fig. 16.2).

i. Include adult Schistosomes and certain microfilariae. Concomitant immunity is shown by rodents on Rhesus monkeys against infection of Schistosoma.

ii. Microfilariae of Wuchereria, Brugia etc. can survive long period in human blood, indi­cating in their normal hosts they invoke very little immune response.

Example: Trichinella spiralis, Echinococcus granulo­sus etc. produce antibodies against tissue nema­tode.

The serious and often fatal results of trichiniasis are due to the offspring of the infecting worms and not to the adult worms in the intestine. The resistance of mice to Trichinella infection can be enhanced by injection of secretions and excre­tions of Trichinella larvae and adults. T. spiralis arctica is essentially incapable of infecting rats but readily infects mice, deer and certain carnivores.

i. Hosts can inhibit totally or partially the establishment of the parasitic develop­ment of Cooperia curticei in sheep.

ii. Parasites develop anatomic abnormalities along with oedema and necrosis, decreased albumin levels and significant reduction in weight gain and often death follows e.g. Ostertagia sp. It fails to develop a vulvar flop in calves.

iii. Parasite does not grow as rapidly or reach its normal size, e.g., Trichinella spiralis in man.

iv. Parasite’s life-cycle is altered, e.g. Strongyloides sp., in naive pigs etc.

Antibodies, although, do not generally cause the death of adult worms but affected worms undergo retarded growth with destrobilisation.

Protective Immunity is absent in case of tissue trematodes like Fasciola sp., Paragonimus westermani etc.

Endoparasites, both protozoans and helminths can survive long dura­tions in immunologically hostile environments. Such parasites are immunologically inert because they produce immunogens which are antigenic, similar to those of the hosts so that they are recognised as ‘self’.

This phenomena of antigen shearing between hosts and parasites is called molecular mimicry.

There are three possibilities regarding its origin:

(i) Mimicry by natural selection,

(ii) Mimicry by host induc­tion, and

(iii) Mimicry resulting from incorpora­ted host antigens (Fig. 16.4).

Effects of parasitism on parasites:

The para­sites undergo elaborate adaptations in order to harmonize with the host.

This adaptation takes place by two ways as follows:

(a) Degeneration of organ system:

i. Sense organs are poorly developed.

ii. Less developed locomotory organs.

iii. Intestinal parasites have no well-developed digestive organs, e.g., in Taenia solium there is complete loss of digestive tract.

(b) Specialization: New attainment of organs or systems:

1. In External parasites:

i. Compressed bodies with backwardly pro­jecting spines for attachment, e.g., Flea.

ii. Tactile hairs in mites.

iii. Barbed proboscis in ticks.

The ectoparasites also show degeneration in the following organs:

i. Loss of eyes and sometimes sense organs.

iii. Sometimes reduction of legs.

2. In Internal parasites:

The endoparasites possess peculiar admixture of both degene­rated and specialised parts as follows:

i. They possess all sorts of hooks, barbs, suckers as organs for attachment, although they have lost sense organs or special organs for locomotion.

ii. Very simple nervous system and some­times complete loss of digestive systems.

iii. The most remarkable specialization of the endoparasites brought forth in their repro­ductive systems which enabled them to a greater power of reproduction. For them every structure, every function, and every instant of their life are modified to a certain extent for the sole purpose of reproduction.

“A fluke does not eat to live”—it lives and thus eats only for reproduction. The highest spe­cialization of reproductive system is achieved by the tapeworm. In the mature proglottids both male and female reproductive organs are present in tapeworm while others (proglottids) contain either male or female reproductive systems.

Host susceptibility and specificity:

For a parasite to live habitually in a host-body there must be:

i. Suitable conditions for the transmission of parasites from one host to another

ii. Able to establish itself in a host when it reaches a new one

iii. Satisfactory conditions for growth and reproduction after its establishment.

Hosts and Parasites: A mutual tolerance:

In course of time, a mutual adjustment or tole­rance frequently develops between the two (2)— host and parasite, which results to lead their life as a sort of compound organisms, without any serious effect to either. It may not” be in the best interest of the parasites to destroy its host for it would do it—invariably it would destroy itself.

Thus, parasitism is a specialised mode of living within a broader ecological category— symbiosis. In parasitism—the host and the para­site have a very intimate association where all the benefits are derived by the parasites from its prey—the host and the two (2) systems constantly interacting with each other.

Thus the criticism of the story—”Host- Parasite Interaction” is one of the compromise—a key (parasite) to unlock the box (host) of an unrevelled mysterious entity—in which the parasites making elaborate efforts to overcome the match against the host while the host making attempts to keep the ball in the goal of parasites, thus trying to eradicate it.


Biology

The protozoan parasite, Trypanosoma cruzi, causes Chagas disease, a zoonotic disease that can be transmitted to humans by blood-sucking triatomine bugs.

Life Cycle:

An infected triatomine insect vector (or &ldquokissing bug&rdquo) takes a blood meal and releases trypomastigotes in its feces near the site of the bite wound. Trypomastigotes enter the host through the wound or through intact mucosal membranes, such as the conjunctiva . Common triatomine vector species for trypanosomiasis belong to the genera Triatoma, Rhodnius, and Panstrongylus. Inside the host, the trypomastigotes invade cells near the site of inoculation, where they differentiate into intracellular amastigotes . The amastigotes multiply by binary fission and differentiate into trypomastigotes, and then are released into the circulation as bloodstream trypomastigotes . Trypomastigotes infect cells from a variety of tissues and transform into intracellular amastigotes in new infection sites. Clinical manifestations can result from this infective cycle. The bloodstream trypomastigotes do not replicate (different from the African trypanosomes). Replication resumes only when the parasites enter another cell or are ingested by another vector. The &ldquokissing bug&rdquo becomes infected by feeding on human or animal blood that contains circulating parasites . The ingested trypomastigotes transform into epimastigotes in the vector&rsquos midgut . The parasites multiply and differentiate in the midgut and differentiate into infective metacyclic trypomastigotes in the hindgut .

Trypanosoma cruzi can also be transmitted through blood transfusions, organ transplantation, transplacentally (from mother to unborn baby), and in laboratory accidents.


6 CLINICAL IMPLICATIONS OF GENETIC DATA

Despite the plethora of findings about genetic risk factors, the overall picture is that most of these genes are likely to have a relatively limited impact on infection risk, suggesting that many of them are involved in response to viral infection. This fact makes predicting which people will have a severe reaction to SARS-CoV-2 somewhat difficult. Moreover, relatively little is understood about inter-individual genetic differences in the immune response to this novel coronavirus, or the pleiotropic effects that different variants might confer (Godri Pollitt et al., 2020 ).

Nevertheless, the goal of ongoing COVID-19 research is to identify genetic variation that will improve the clinical management of this disease and foster better patient outcomes (Murray et al., 2020 The COVID-19 Host Genetics Initiative, 2020 ). For example, of the 68 severe COVID-19 risk-associated genes identified by Taylor et al. ( 2020 ), several of them yield protein products that can be targeted for drug development, with drugs for nine of these targets having reached Phase I clinical trials. Others have suggested that “[p]airing HLA typing with COVID-19 testing where feasible could improve assessment of viral severity in the population” (Nguyen et al., 2020 : e00510), thereby allowing prioritization of individuals with high-risk HLA types for vaccination. Likewise, knowing the levels of ACE2 and TRPRSS2 expression in asthma patients who use inhaled corticosteroids and those who do not will help clinicians identify subgroups such as males, African Americans and patients with diabetes that are at higher risk for COVID-19 morbidity (Peters et al., 2020 ). Verdecchia et al. ( 2020 ) further point to the possible use of recombinant ACE2, angiotensin 1-7 and AT1 receptor blockers to help treat patients with SARS-CoV-2 infection.

All of the emerging knowledge about genetic risk factors for infection is fueling global research on vaccines for COVID-19, with over 145 vaccines being developed and 19 currently being used in human clinical trials (Coronavirus Vaccine Tracker, 2020 ). Yet, while an effective and affordable vaccine will certainly go a long way to halting the current pandemic, other more basic public health measures such as mask wearing, social distancing, COVID-19 testing, and contact tracing will be essential for mitigating the impact of coronavirus on the general public for the foreseeable future, and particularly in communities of color who are at much higher risk for viral exposure and severe disease expression (Oppel Jr., Gebeloff, Lai, Wright, & Smith, 2020 ).


Important Metrics

Title Cell Host and Microbe
Publication Type Journal
Subject Area, Categories, Scope Cancer Research (Q1) Immunology and Microbiology (miscellaneous) (Q1) Microbiology (Q1) Molecular Biology (Q1) Parasitology (Q1) Virology (Q1)
h-index 182
Overall Rank/Ranking 125
SCImago Journal Rank (SJR) 7.985
Impact Score 13.38
Publisher Cell Press
Country United States
ISSN 19313128


Stage 3: Hypoxia, ground glass infiltrates, and progression to ARDS

Unfortunately, about 20% of the infected patients will progress to stage 3 disease and will develop pulmonary infiltrates and some of these will develop very severe disease. Initial estimates of the fatality rate are around 2%, but this varies markedly with age [1]. The fatality and morbidity rates may be revised once the prevalence of mild and asymptomatic cases is better defined. The virus now reaches the gas exchange units of the lung and infects alveolar type II cells. Both SARS-CoV and influenza preferentially infect type II cells compared to type I cells [11, 12]. The infected alveolar units tend to be peripheral and subpleural [13, 14]. SARS-CoV propagates within type II cells, large number of viral particles are released, and the cells undergo apoptosis and die (figure 1) [8]. The end result is likely a self-replicating pulmonary toxin as the released viral particles infect type II cells in adjacent units. I suspect areas of the lung will likely lose most of their type II cells, and secondary pathway for epithelial regeneration will be triggered. Normally, type II cells are the precursor cells for type I cells. This postulated sequence of events has been shown in the murine model of influenza pneumonia [15, 16]. The pathological result of SARS and COVID-19 is diffuse alveolar damage with fibrin rich hyaline membranes and a few multinucleated giant cells [17, 18]. The aberrant wound healing may lead to more severe scarring and fibrosis than other forms of ARDS. Recovery will require a vigorous innate and acquired immune response and epithelial regeneration. From my perspective, similar to influenza, administrating epithelial growth factors such as KGF might be detrimental and might increase the viral load by producing more ACE2 expressing cells [19]. Elderly individuals are particularly at risk because of their diminished immune response and reduced ability to repair the damaged epithelium. The elderly also have reduced mucociliary clearance, and this may allow the virus to spread to the gas exchange units of the lung more readily [20].

Human alveolar type II cells infected with SARS-CoV. Human type II cells were isolated, cultured in vitro, and then infected with SARS-CoV. Viral particles are seen in double membrane vesicles in the type II cells (a) and along the apical microvilli (b). Reproduced with permission from the American Thoracic Society [8].

There are significant knowledge gaps in the pathogenesis of COVID-19 that will be filled in over the next few months. I based my comments on the assumption that viral entry by SARS-CoV-2 will be the same as SARS-CoV. We do not know if there are alternate receptors for viral entry. CD209L is an alternative receptor for SARS-CoV [21]. We await detailed studies on infection and the innate immune response of differentiated primary human lung cells. The apical cilia on airway cells and microvilli on type II cells may be important for facilitating viral entry.

In conclusion, COVID-19 confined to the conducting airways should be mild and treated symptomatically at home. However, COVID-19 that has progressed to the gas exchange units of the lung must be monitored carefully and supported to the best of our ability, as we await the development and testing of specific antiviral drugs.



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