Immunomicrobiology

IMMUNOMICROBIOLOGY
(see also Homo sapiens diseases : infectious aetiology

)

Host-pathogen interactions involve multiple molecular recognition events involving one or more components encoded by the pathogen (let's call them P) and one or more components encoded by the host (let's call them H). It is important to distinguish between 2 alternative evolutionary scenarios that led to these interactions :

resistance against infection by the host : H evolved to recognize P, while P evolved to perform functions unrelated to host-pathogen interactions. In this scenario, H is typically a pathogen recognition receptor (PRR) and P is a pathogen-associated molecular pattern (PAMP). In animals with adaptive immune systems, H can also be an antigen receptor, in which case P can be any microbial antigen.

genomunity : genetically inherited, acquired or induced state of resistance to a specific pathogen

the host and the microorganism both benefit from an interaction : P and H may have coevolved to interact twith each other.
productive infection by the pathogen : P evolved to recognize H, while H evolved to perform functions unrelated to this interaction. In this case P is usually referred to as a virulence / pathogenicity factors / determinants / aggressins

Although the majority of animals and plants, including humans, are dominated by the diploid phase of their life cycle, extensive diversity in ploidy level exists among eukaryotes, with some groups being primarily haploid whereas others alternate between haploid and diploid phases. Previous theory has illuminated conditions that favor the evolution of increased or decreased ploidy but has shed little light on which species should be primarily haploid and which primarily diploid. A discovery emerged from host-parasite models in which ploidy levels were allowed to evolve: selection is more likely to favor diploidy in host species and haploidy in parasite species. Essentially, when parasites must evade a host's immune system or defense response, selection favors parasitic individuals that express a narrow array of antigens and elicitors, thus favoring haploid parasites over diploid parasites. Conversely, when hosts must recognize a parasite before mounting a defensive response, selection favors hosts with a broader arsenal of recognition molecules, thus favoring diploid hosts over haploid hosts. These results are consistent with the predominance of haploidy among parasitic protists^ref. If diploidy is good for resistance, it seems to me that these models suggest that triploidy and tetraploidy and heptaploidy and so forth would be even better for a host. It's kind of diminishing returns, though. At one point, if you've already recognized and cleared your parasite, then having even more genes doesn't help you that much more. And there can be costs to having higher ploidy levels

Evasion from immune systems

from innate immune system

avoiding acidic pH in stomach

living in watery food allows high speed flow
pH buffering

living in basic food (eg HCO₃^--rich milk or His-rich proteins)
having enzymes producing buffering molecules (eg urease produces NH₄⁺)

resisting flows with epithelial adhesion molecules
evasion of immunosurveillance : persistence at bodily sites inaccessible to phagocytes (including APCs) and lymphocytes. Antigens that do not reach organized lymphatic tissue, irrespective of whether they are derived from self proteins or from infectious agents, not only fail to induce an immune response but are also unable to delete T cells

stay on epidermis (eg human papillomaviruses )
stay in the lumen of empty viscera (GI tract, urinary tract, respiratory tract, mammary gland or kidney tubule)
localization in immune-privileged sites
encystment
endocellular localization into non-phagocytic cells without expose infectious nonself or modify self (e.g. Neisseria spp., Mycobacterium spp., Listeria spp., and Bordetella pertussis enter epithelial cells)
avoid provoking an overwhelming inflammatory response. Some pathogens induce minimal or no inflammation required to focus the phagocytic defenses.
inhibit phagocyte chemotaxis, e.g.

streptolysin from Streptococcus spp. (which also kills phagocytes) suppresses neutrophil chemotaxis, even in very low concentrations
fractions of Mycobacterium tuberculosis are known to inhibit leukocyte migration
Clostridium perfringens q toxin inhibits neutrophil chemotaxis

inhibition of phagocytosis

multicellularity (e.g. mycelia)
hydrophilic polysaccharide capsules of Streptococcus pneumoniae , Haemophilus influenzae , Treponema pallidum and Klebsiella pneumoniae
dedicated surface molecules

M protein and fimbriae (Group A Streptococci)
slime layer (Pseudomonas aeruginosa )
O antigen (Escherichia coli )
K antigen (Escherichia coli ) or the analogous Vi antigen (Salmonella typhi )

decoy ligands for scavenging receptors

protein A (Staphylococcus aureus )

survival inside phagocytes

escape from the phagosome. This is a very clever strategy employed by the Rickettsiae which produce a phospholipase enzyme that lyses the phagosome membrane within 30 seconds after ingestion. Gram-negative Salmonella typhimurium bacteria are normally present in vacuoles inside infected host cells, but a small percentage escape these vacuoles and enter the cytosol : polyubiquitylated proteins are found on the surface of cytosolic, but not vacuolar or extracellular, macrophage cultures. Proteasomes are recruited to cytosolic S. typhimurium 4 hours after invasion : proteasome inhibitors significantly increased the number of intracellular bacteria and prevent presentation of bacterial peptides on MHC class I molecules^ref.
inhibition of fusion of the phagocytic lysosomes (granules) with the phagosome. This is the strategy employed by Salmonella spp., Mycobacterium tuberculosis , Legionella spp. and the Chlamydia spp.
survival inside the phagolysosome: it may be due to the surface components of the bacteria or due to extracellular substances that they produce which interfere with the mechanisms of phagocytic killing (e.g.

catalase activity competes with myeloperoxidase activity
Mycobacterium spp. inhibit nitric oxide synthase recruitment to phagosomes during macrophage infection^ref and PGL-1 and LAM are R.O.S. buffers

Listeria monocytogenes avoid the ubiquitin system by their movement inside cells using host polymeric actin-rich ‘tails’ that are not recognized by the ubiquitin system, and this mechanism could apply to other bacteria that are adapted to life in the cytosol and use actin-based motility such as Shigella flexneri ^ref

... rest into the phagocyte until better growth conditions occur (e.g. Mycobacterium tuberculosis , Salmonella spp., Listeria monocytogenes , Legionella pneumophila , Brucella melitensis , Ajellomyces capsulatus , Leishmania donovani , Trypanosoma cruzi ).
... replicate in the phagocyte (e.g. Brucella abortus)

products that kill or damage phagocytes ...

... before ingestion

Streptococcus

Staphylococci

Pseudomonas aeruginosa,

... after ingestion. They may grow in the phagosome and release substances which can pass through the phagosome membrane and cause discharge of lysosomal granules, or they may grow in the phagolysosome and release toxic substances which pass through the phagolysosome membrane to other target sites in the cell (e.g Mycobacterium spp., Brucella spp., Listeria spp.).

non-hydrolysable biopolymers (e.g. cellulose, chitin, b-glucan)
inhibition of factor(s) of non-classical complement cascades

from adaptive immune system

imparing antibody-mediated immunity (AMI)

induction of secretions that dilute Abs and complement factors
induction of ineffective antibody : many types of antibody are formed against a given Ag, and some bacterial components may display various antigenic determinants. Low avidity or "ineffective" (non-neutralizing) Abs might even aid a pathogen by combining with a surface Ag and blocking the attachment of any functional Abs that might be present.
inhibition of factor(s) of classical complement cascade
Abs absorbed by soluble bacterial Ags
Ig proteolysis or fabulation : the nonfunctional Fab fragments generated from Ig proteolysis bind epitopes and protect the invader from further recognitions by complete Ig molecules.
detachment of cell-bound immunocomplexes by releasing the antigens

impairing cell-mediated immunity (CMI)

down-regulation of MHC I and/or II molecules expression (eg HCMV )
high zone tolerance (high persistent doses of circulating Ag leading to clonal exhaustion) (eg for DOCILE or Cl-13 Armstrong strains of LCMV ^Ref1,
Ref2,)
generalized immunosuppression

cell killing (e.g. leukocidins)
inhibition of all T_h lymphocytes (e.g. HIV)

polyclonal activation of lymphocytes

clones of B cells cytotoxic for other lymphocytes
activation of T_Reg lymphocytes => inhibition ot T_h1 lymphocytes

sustained exposure to bacterial antigens from heat-killed Porphyromonas gingivalis is sufficient to induce TcR z chain downregulation and impair T-cell function, provided an IFN-dependent T_h1 immune response developed. This could be a physiological response that attenuates an exacerbated immune response: however, it can act as a 'double-edged sword', impairing immune responses to chronic diseases.

imparing both AMI and CMI

antigenic disguise : Bacteria may be able to coat themselves with

host proteins

Staphylococcus aureus produces cell-bound coagulase which clots fibrin
Treponema pallidum binds fibronectin to its surface
antibody molecules

host polysaccharides

sialic acid
Group A Streptococci are able to synthesize a capsule composed of hyaluronic acid.

immunological tolerance

immunological incompetence (fetal exposure to Ag) : noncytopathic hepatitis viruses have co-evolved with humans to infect offsprin at birth via infected blood from carrier mothers. By infecting at a time when immune responsiveness of the newborn is virtually absent, disease-causing immunopathology is avoided or reduced to a level compatible with survival of the host
molecular mimicry (e.g. some bacterial capsules are composed of polysaccharides (hyaluronic acid, sialic acid) so similar to host tissue polysaccharides that they are not immunogenic)

antigenic variation has always been seen as an adaptation of the parasite to evade host defence: the coordination necessary for the success of this strategy might be provided by the host. Short-lived, partially cross-reactive immune responses to malaria-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections^ref

gene switching (stage-specific Ags) : they allow 1 only complete replicative cycle occurs
antigenic drift : mutations in surface antigens (e.g. Borrelia recurrentis , Influenzaviruses , HIV-1 ) they allow many complete replicative cycles occur
antigenic shift : e.g. genetic reassortment in Influenzaviruses

Web resources

American Society for Microbiology of USA (ASMUSA) : Division E - Immunology
Center 1: Virology, Immunology and Infectious Disease Research at Children's National Medical Center (CNMR)
Institute of Infection and Immunity (III) at Nottingham University, UK
Laboratory of Bacterial Pathogenesis and Immunology
Loyola University Chicago
Microbiology and Immunology On-Line by A.Ghaffar, G.Mayer, W.Bowers and R.Hunt at University of South Carolina, USA
MBChB Infection and Immunity by Colin Hewitt at University of Leicester
Microbiology, Immunology and Parasitology at Louisiana State University Medical Center
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