Why do pathogens have antigens

For example, Brucella abortus preferentially targets marginal zone B cells in the mouse spleen B cells infected with B. Intriguingly, brucellosis is more rapidly cleared in B cell-deficient mice owing to a reduction in the levels of IL and an increase in protective T cell responses, suggesting that B.

Salmonella enterica subsp. Typhimurium might use the bone marrow as a long-term infection niche Following the in vitro infection of human blood lymphocytes with S.

Typhimurium, bacteria are found inside IgM-producing memory B cells. Infection of these cells results in B cell activation and the induction of specific antibody production, but also leads to increased survival and intracellular persistence of bacteria in infected B cells Several mechanisms have been described for the internalization of bacteria by B cells.

For example, a role for phagocytosis of B. The BCR can also be involved in bacterial internalization by B cells. By contrast, internalization of S. Typhimurium into B cells has been reported to involve interaction with an antigen-specific BCR Typhimurium pathogenicity island 1 and 2, respectively ; the number of intracellular bacteria found in B cells was substantially reduced when the bacterial T3SS was made non-functional Typhimurium forces its entry into B cells by triggering active invasion processes More recently, Shigella flexneri was also shown to invade human B cells in a process that is dependent on the T3SS but independent of B cell-mediated phagocytosis, as only bacteria carrying a functional T3SS were found inside B cells, both in vitro and in an ex vivo intestinal infection model Long-lived plasma cells and memory B cells normally constitute the B cell compartment and provide protection from reinfection.

However, some pathogens have been reported to deliberately induce short-lived, polyclonal plasma cells in order to dilute long-lived, specific antibody responses.

The activity of the parasite-produced trans -sialidase is dependent on Bruton's tyrosine kinase BTK This results in lower affinity, lower neutralizing activity and lower complement-mediated toxicity of E2-specific antibodies 57 , Dashed arrows indicate normal pathways that are weakened or impaired during infection. Taken together, these studies show that the entry of pathogenic bacteria into B cells is not only mediated by phagocytosis, but can also involve active invasion processes mediated by bacterial secretion systems.

This process is similar to those used by certain viruses, such as EBV that target specific host cell populations through the expression of viral glycoproteins. Together, these data demonstrate that some pathogens have evolved mechanisms to force their entry into B cells, leading to the establishment of intracellular reservoirs.

Besides using B cells as a reservoir, some pathogens have evolved mechanisms to interfere with immune signalling and B cell differentiation to impair the maturation of B cells into protective memory B cells and plasma cells Table 1. Diversion of B cell maturation by parasites. During infection, parasites can modulate B cell responses and stimulate the production of low-affinity antibodies, which, in some cases, has been associated with the dilution of specific, long-lived antibodies Fig.

For example, Trypanosoma cruzi , the causative agent of Chagas disease, attacks B cells at different developmental stages, depleting immature B cells during their development in the bone marrow but also inducing polyclonal expansion of mature B cells in the spleen, which is thought to allow the parasite to avoid B cell-mediated responses and to persist in the host 42 , Indeed, nonspecific B cell activation can be triggered by a variant antigen of the Trypanosoma spp.

Additionally, certain cytosolic and secreted proteins, such as T. The exact mechanisms of B cell activation by parasitic T cell-independent antigens are often unknown, but the activation of B cells by the T. Interestingly, trans -sialidase also induces the secretion of the pro-inflammatory cytokine IL by B cells, in a process that involves the activation of BTK and SRC kinases in conjunction with the expression of CD45 by B cells B cell production of IL was shown to have an immunoregulatory role during T.

Therefore, trans -sialidase seems to have a dual role during infection by promoting both the production of non-protective antibodies and the induction of regulatory B cells.

Leishmania major also affects B cell differentiation, which results in the generation of immunosuppressive regulatory B cells. Furthermore, adoptive transfer of regulatory B cells induced following L.

However, only a few studies have addressed how regulatory B cells are induced by direct contact with Leishmania spp. For example, antigens that induce IL production by mouse spleen B cells in vitro include soluble proteins, such as Leishmania infantum tryparedoxin, or sugars, such as lacto- N -fucopentaose III, which is found on soluble egg antigens of L. However, the B cell signalling pathways involved in this process are unknown.

A number of pathogens have been reported to induce the differentiation of regulatory B cells to suppress protective immune responses. IL has recently been shown to have a role in B cell regulatory function during S. Typhimurium infection Diversion of B cell maturation by viruses. The induction of B cell activation leading to polyclonal antibody responses that dilute the production of specific antibodies has also been reported as a strategy used by several viruses to skew protective immune responses Fig.

Whereas the early immune response to some viruses, such as influenza virus, mediates protection, antibodies generated in response to hepatitis C virus HCV infection fail to clear the virus in patients with persistent infections and lymphoproliferative disorders such as B cell lymphomas 55 , This was shown by incubating B cells with HCV E2 protein in vitro , but was also directly linked to the observation that B cells infected in vivo show higher expression of activation markers Additionally, E2 binding and subsequent viral infection of B cells induces the upregulation of AID and SHM of the immunoglobulin heavy chain in hybridoma cell lines that produce E2-specific antibodies, resulting in the production of antibodies with lower affinity, lower neutralizing capacity and lower complement-mediated toxicity, and this could explain why, in patients, serum HCV-specific antibodies fail to neutralize the virus Therefore, HCV is an intriguing example of how normal B cell maturation can be 'hijacked' by viruses to induce diluted antibody responses Fig.

HIV-1 infection is also associated with B cell dysregulation and exhaustion of the B cell compartment. This interaction, in conjunction with activation of B cell activating factor BAFF signalling, induces the production of polyclonal antibodies independently of T cell help Interestingly, Nef shuttles from infected macrophages to B cells by hijacking long-range intercellular conduits, such as nanotubules, which allows HIV-1 to inhibit CSR in lymphoid follicles in vivo Taken together, these studies highlight how direct interaction between HIV-1 and B cells induces a shift from the production of T cell-dependent specific antibodies to the production of nonspecific antibodies in a T cell-independent manner, thereby promoting viral immune escape Fig.

The induction of regulatory B cells also contributes to immune escape during viral infections, as reported for cytomegalovirus, hepatitis B virus and HIV-1 Refs 63 , 64 , 65 Table 1.

However, mechanistic insight into the induction of regulatory B cells by these viruses is limited. Interestingly, following infection with polyoma virus, IL production by B cells is induced by virus-like particles in a TLR4-dependent manner, suggesting that this pathway might be involved in the generation of regulatory B cells 66 Fig.

Diversion of B cell maturation by bacteria. Similarly to parasites and viruses, bacteria also trigger polyclonal activation of B cells to impair protective immune responses mediated by the production of specific antibodies Fig. For example, mouse models of infection with Ehrlichia muris and Borrelia burgdorferi are characterized by T cell- and GC-independent expansions of non-switched, IgM-secreting plasma cells, which impairs the development of a protective antibody response 67 , Similarly, binding of the M.

TLR9 signalling is also involved in the proliferative and IgM-producing response of human polyclonal IgD memory B cells during Neisseria gonorrhoeae infection in vitro. Notably, this response is specific to N. In addition to the dilution of the specific antibody response, which results from polyclonal B cell activation, bacteria can produce virulence effectors that directly manipulate B cell signalling pathways. Anthrax lethal toxin from the Gram-positive Bacillus anthracis directly binds to B cells by the anthrax protective antigen and is able to cleave mitogen-activated protein kinase kinases MAPKKs through the lethal factor protease, which results in the inhibition of B cell proliferation and immunoglobulin production, both in vitro and in vivo Similarly, several Gram-negative bacteria use T3SSs to deliver virulence effectors into the host cell cytoplasm and manipulate B cell functions.

For example, following infection with Yersinia pseudotuberculosis , primary B cells isolated from the spleens of hen egg lysozyme HEL -specific immunoglobulin-transgenic mice showed reduced activation upon stimulation with their cognate antigen Through the use of bacterial mutants, the authors showed that the impairment of B cell activation was T3SS-dependent and identified the tyrosine phosphatase YopH as the bacterial virulence effector responsible for this phenomenon.

Intracellular bacteria such as Chlamydia abortus , B. Typhimurium can also affect ongoing immune responses by favouring the generation of immunosuppressive regulatory B cells 8 , 15 , 16 Fig. Typhimurium infection, suggesting that these signalling pathways are directly activated by the bacterium, repressing protective innate immune responses 16 Fig. Additionally, IL has recently been shown to contribute to B cell regulatory function during S. Collectively, these studies show that pathogens use two main strategies to divert B cell maturation and impair protective immune responses: the induction of short-lived plasma cells which secrete antibodies of low affinity, leading to the dilution of specific, long-lived antibody responses Fig.

In addition to living inside B cells and manipulating B cell maturation, pathogens can influence B cell responses by modulating the intricate balance of pathways that determines whether a B cell lives or dies Fig. Several pathogens have been reported to directly interfere with B cell survival and death pathways. By contrast, translocation of the virulence factor CagA leads to extracellular signal-regulated kinase ERK and mitogen-activated protein kinase MAPK phosphorylation and induction of the anti-apoptotic protein B cell lymphoma 2 BCL-2 , thereby preventing B cell death 87 , Manipulation of B cell survival by parasites.

Both Trypanosoma brucei and T. In mice, T. Similarly to Trypanosoma spp. However, whether B cell death occurs owing to direct contact with Trypanosoma spp. Interestingly, T. These parasites also induce the dilution of antibody responses, and their effect on B cells seems to be dependent on the B cell subpopulation that is targeted.

Therefore, Trypanosoma spp. Manipulation of B cell survival by viruses. Viruses that cause the development of B cell lymphomas often have the capacity to directly increase B cell survival 59 , 78 , 79 Table 1. Whereas EBV persists intracellularly in B cells, where it hides from antibody responses, HCV can induce non-protective antibody responses and lymphoproliferative disorders.

These two viruses provide an intriguing example of how the induction of B cell survival can facilitate infectious processes. In contrast to viruses that induce B cell survival, influenza A virus leads to the induction of B cell death. Mouse B cells carrying a BCR specific for influenza haemagglutinin were found to be infected in vitro and in vivo in the lungs, failed to produce antibodies and ultimately died These data suggest that targeting of antigen-specific B cells at the infectious site could be an efficient mechanism to impair or delay the adaptive immune response to infection.

Manipulation of B cell survival by bacteria. Similarly to viruses and parasites, bacterial pathogens can manipulate the survival and cell death pathways of B cells Table 1. For example, Listeria monocytogenes infection results in high cytotoxicity for B cells. Interestingly, L. Apoptosis of B cells in vitro has also been described following infection with Francisella tularensis Similarly to F. Interestingly, induction of apoptosis in uninfected B cells requires a functional T3SS, but is independent of the translocation of T3SS-dependent virulence effectors.

Instead, the virulence effector IpaD — the needle-tip protein of the Shigella spp. The presence of an as yet unidentified bacterial co-signal or multiple co-signals is necessary for the triggering of IpaD-mediated cell death, as apoptotic B cells were only detected when cells were co-incubated with IpaD and non-pathogenic S.

Notably, the co-incubation with non-pathogenic bacteria results in the loss of both mitochondrial membrane potential and the upregulation of mRNA encoding TLR2. Shigella spp. Helicobacter pylori infection has also been shown to lead to translocation of AIF and induction of apoptosis in a B cell line, which has been associated with the persistence of H.

By contrast, translocation of the H. Whereas the induction of apoptosis has been suggested to facilitate persistence by deletion of protective B cells, the increased survival of B cells has been associated with H. Whether one or both of these mechanisms occur in vivo in infections with H. In contrast to bacteria that induce B cell death, S. Typhimurium induces B cell survival, which has been suggested to benefit the bacterium as it uses B cells as a survival and dissemination niche Notably, S.

Typhimurium infection, which prevents activation of the inflammasome and the induction of cell death Interestingly, inhibition of the inflammasome occurs in both infected and uninfected cells and requires the S.

Together, these studies highlight that pathogens can interfere with both survival and cell death pathways in B cells. Interestingly, pathogens that use B cells as a niche for survival or dissemination or that divert B cell maturation often increase B cell survival, presumably to facilitate their persistence in the host.

Acute, recurrent infections, however, are often accompanied by B cell death and impaired protective immune responses, suggesting that reinfection is facilitated by the deletion of the cell population that confers protective immunity. Increasing evidence is emerging that several pathogenic parasites, viruses and bacteria interact directly with and manipulate B cells.

Such direct targeting, in addition to the indirect effect of the infection-induced local microenvironment, illustrates the diversity of mechanisms used by pathogens to evade host protective immunity.

Pathogens manipulate B cells using three main strategies: the use of B cells as a reservoir, the diversion of B cell maturation either by the induction of short-lived plasma cells that secrete antibodies of low specificity or by the induction of immunosuppressive regulatory B cells , and the modulation of B cell survival. Interestingly, some pathogens use multiple mechanisms simultaneously to ensure their survival.

For example, several viruses that cause persistent infections induce B cell survival, which can result in lymphoma formation. Although it seems detrimental to the viruses to induce the survival of B cells, these viruses have often found ways to hide from or subvert the antibody response in order to persist within the host.

By contrast, in the case of acute infections or host-restricted pathogens, pathogens have evolved mechanisms to facilitate reinfection. For instance, by inducing B cell death, S. Typhimurium suppresses immune responses by a different mechanism involving the induction of regulatory B cells, which modulate protective responses mediated by T cells and other innate immune cells 16 , Regulatory B cells have received increasing attention and are also induced in several viral and parasitic infections.

Although these cells show therapeutic potential in the treatment of autoimmune diseases, further insight into the mechanisms by which regulatory functions are triggered is needed to provide information on how to prevent their detrimental effects following infections. To elucidate cellular mechanisms of B cell manipulation by pathogens, a combination of in vitro and in vivo studies seems particularly promising.

For instance, a recent study using human and mouse norovirus strains elegantly shows that B cells provide a cellular target for the virus in vitro and in vivo , and that infection is promoted by enteric bacteria expressing histo-blood group antigen Notably, pathogens are often used as a simple tool for deciphering the generation of immune cell functions, but recent evidence highlights their ability to divert immune responses by expressing key virulence factors.

New approaches are thus needed to gain insights into the role of such weapons in infections. For instance, a fluorescence resonance energy transfer FRET -based assay to directly monitor the delivery of virulence effectors into host cells was recently used to investigate whether B cells are deliberate targets of T3SS-bearing bacteria in vitro and in vivo 91 , 92 , 93 , The identification of key virulence factors diverting host responses could also affect vaccine design, especially for live attenuated vaccine candidates, which involve the identification and deletion of virulence factors that have a negative effect on the host-protective immune responses.

For example, the S. The recent demonstration that IpaD induces B cell death, but only in the presence of bacterial cofactors 41 , suggests that IpaD-specific antibodies elicited upon immunization would not only prevent cell invasion but also the induction of B cell death triggered during infection. Therefore, an IpaD-based subunit vaccine seems particularly promising in the fight against S. Additionally, systems biology approaches targeted at detecting infection and vaccination signatures in people may help us to gain insights into how protective immune responses are established.

For example, systems analysis and bioinformatics integration of various 'omics' approaches, in combination with traditional experimental approaches, have contributed to a better characterization of the host immune response against West Nile virus infection To combine such an analysis with insights into manipulation strategies used by pathogens would substantially increase our knowledge of how protective B cell responses are elicited and diverted during particular infections, which may lead to novel therapeutic and vaccination approaches in the future.

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The Plasmodium falciparum -specific human memory B cell compartment expands gradually with repeated malaria infections. PLoS Pathog. By comparing the protective immune response to malaria infection with a tetanus vaccine, this publication shows that the induction of B cell antibody production can be diverted during pathogenic infections. To fight infections, the immune system must be able to identify pathogens.

Pathogens have molecules called antigens on their surface. When a pathogen gets into the body, the immune system reacts in 2 ways. The innate immune response is a rapid reaction. Innate immune cells recognize certain molecules found on many pathogens. These cells also react to signaling molecules released by the body in response to infection.

Through these actions, innate immune cells quickly begin fighting an infection. This response results in inflammation. The cells involved in this reaction can kill pathogens and can also help activate cells involved in adaptive immunity.

The adaptive immune response is slower than the innate response but is better able to target specific pathogens. There are 2 main cell types involved in this response: T cells and B cells.

Some T cells kill pathogens and infected cells. Other T cells help control the adaptive immune response. The main function of B cells is to make antibodies against specific antigens. Antibodies, also known as immunoglobulins, are proteins that attach themselves to pathogens. This signals immune cells to destroy the pathogen.

It takes time for T and B cells to respond to the new antigens when a pathogen causes an infection. Once exposed to the pathogen, these cells develop a memory for the pathogen so that they are ready for the next infection.

As part of the adaptive immune response, some T and B cells change into memory cells. If a person becomes infected with the same pathogen again, these cells are able to quickly and vigorously begin fighting the infection. Immunodeficiency results when the body does not have enough of certain kinds of immune cells or the cells do not function properly.

When that happens, a person is more vulnerable to infections. Immunodeficiency can be primary genetic or secondary due to other conditions. White blood cells can also produce chemicals called antitoxins which destroy the toxins poisons some bacteria produce when they have invaded the body. Tetanus, diphtheria and scarlet fever are all diseases where the bacteria secrete toxins. The memory cells remember the microbe which caused the disease and rapidly make the correct antibody if the body is exposed to infection again.

The pathogen is quickly destroyed preventing symptoms of the disease occurring. Microbes that cause disease are called pathogens. Find out which microbe is responsible for malaria! Homepage Why Microbiology Matters What is microbiology? Microbes and the human body Immune system. Immune system An infection can be seen as a battle between the invading pathogens and the host. First line of defence The first line of defence is non-specific and aims to stop microbes from entering the body.

Second line of defence If microbes do manage to get inside the body then the second line of defence is activated.

Third line of defence The third and final line of defence is the immune response. Once the invading microbes have been destroyed the immune response winds down.

Microbes and disease Microbes that cause disease are called pathogens. Routes of transmission Find out how you can pick up germs and pass them on to others.

Vaccination Just a shot in the arm — what do vaccines do? Antibiotics Antibiotics are powerful medicines that only fight bacterial infections.