1. Top of page
  2. Summary
  3. Introduction
  4. Animal models of heterologous immunity
  5. Heterologous immunity in humans
  6. Therapeutic implications and future research
  7. References

Antecedent or current infections can alter the immunopathologic outcome of a subsequent unrelated infection. Immunomodulation by co-infecting pathogens has been referred to as ‘heterologous immunity’ and has been postulated to play a role in host susceptibility to disease, tolerance to organ transplant, and autoimmune disease. The effect of various infections on heterologous immune responses has been well studied in the context of shared epitopes and cross-reactive T cells. It has been shown that prior infections can modulate protective immunity and immunopathology by forming a pool of memory T cells that can cross-react with antigens from heterologous organisms or through the generation of a network of regulatory cells and cytokines. While it is not feasible to alter a host's history of prior infection, understanding heterologous immune responses in the context of simultaneous unrelated infections could have important therapeutic implications. Here, we outline key evidence from animal and human studies demonstrating the effect of heterologous immunity on the outcome of disease. We briefly review the role of T cells, but expand our discussion to explore other immune mechanisms that may modulate the response to concurrent active infections. In particular, we underscore the role of the innate immune system, polarized responses and regulatory mechanisms on heterologous immune responses.


  1. Top of page
  2. Summary
  3. Introduction
  4. Animal models of heterologous immunity
  5. Heterologous immunity in humans
  6. Therapeutic implications and future research
  7. References

In humans, pathogens rarely infect immunologically naïve hosts. In fact, the maturation of the immune system requires antigenic stimulation that begins in the neonatal period, and perhaps even during gestation. In addition to a history of prior infections, individuals from areas endemic for multiple pathogens are often co-infected with unrelated organisms. Concrete examples of exacerbated pathology related to co-infection in humans, such as the deleterious effect of schistosomiasis on hepatitis C progression (Angelico et al., 1997; Kamal et al., 2000), have led to an increased interest in the study of heterologous immunity.

In animals, experimental studies of host–pathogen interactions usually focus on single organisms infecting naïve hosts. This is a reasonable and expedient approach to mechanistically elucidate complex immune pathways. The exquisite specificity of adaptive immunity suggests that it is possible to have completely distinct responses to unrelated infections. However, there is mounting evidence from animal and human studies that prior or concurrent infections with unrelated pathogens modulate immunopathogenic responses.

Here, we outline experimental and clinical examples of heterologous immunity to unrelated pathogens. Excellent reviews have been published on the crucial role of cross-reactive epitopes and the key role of memory T cells in heterologous immune responses (Welsh and Selin, 2002; Rehermann and Shin, 2005). In this review, we explore an expanded definition of heterologous immunity. We focus on the effect of concurrent active infections on systemic immune responses, and provide evidence showing that, in addition to modifying memory T cell pools, heterologous immune responses may polarize the immune response, induce regulatory pathways, and prime innate responses through the action of systemic cytokines. Although we will address the effect of unrelated pathogens on HIV progression, we do not discuss the directly immunosuppressive effect of HIV. Understanding the immune consequences of simultaneous infection with unrelated pathogens could help develop therapeutic strategies to prevent pathologic responses or potentiate protective immune responses.

Animal models of heterologous immunity

  1. Top of page
  2. Summary
  3. Introduction
  4. Animal models of heterologous immunity
  5. Heterologous immunity in humans
  6. Therapeutic implications and future research
  7. References

Cross-reactive T cells

T cells recognize processed peptides that are presented at the surface of antigen presenting cells (APC) in the grooves of histocompatibility complex (MHC) I and II. The specificity of antigen recognition is determined by both the sequence of the peptide and the allele of the associated MHC molecule. An essential feature of the T cell repertoire is to distinguish self from non-self peptides. However, the frequency of T cells that recognize a foreign peptide must be large enough to ensure a rapid immune response. Experimental data have demonstrated a certain level of degeneracy in T cell recognition (Welsh and Selin, 2002). The T cell receptor has evolved to have an optimum level of cross-reactivity, which represents a compromise between a high frequency of T cells that respond to a single epitope and a level of specificity that minimizes autoimmune responses (Mason, 1998). T cell cross-reactivity occurs when unrelated peptides fit similar MHC motifs and are recognized by the same T cell receptor (Fig. 1, III).


Figure 1. A proposed model for mechanisms of heterologous immunity. I. Activation of antigen presenting cells (APC) by an initial infection leads to a primed innate response upon exposure to a second pathogen. II. Activated APCs secrete cytokines and chemokines that direct T cell differentiation into polarized subsets and influence the type of immune response generated to a second unrelated pathogen. Regulatory T cells secrete cytokines that may suppress APC and T cell function. III. In some instances, antigen-specific memory T cells generated against a prior pathogen cross-react with subsequently infecting organisms.

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Heterologous immunity has been well characterized in the setting of viral infections where cross-reactive CD8 T cells play a prominent role. Studies with heterologous viruses such as lymphocytic choriomeningitis (LCMV), Pichinde (PV), vaccinia (VV) and murine cytomegalovirus (MCMV) have shown that prior infection with one virus modulates the response to a second unrelated virus (Kim et al., 2005). During heterologous challenge, cross-reactive epitopes induce dramatic expansion and activation of cross-reactive memory CD8 T cells (Kim et al., 2002), and selective loss of non-cross-reactive cells (Brehm et al., 2002). Interestingly, heterologous protective immunity is not necessarily reciprocal. For example, LCMV and PV infections protect against VV infection, but prior exposure to VV does not induce immunity to either LCMV or PV (Selin et al., 1998).

Cross-reactive T cell responses are not always protective and, in some cases, may enhance immunopathology (Selin et al., 1998; Chen et al., 2001; 2003). In organ transplantation, activation of memory T cells may be particularly deleterious. It has been postulated that the clinical failure of tolerance protocols developed in murine models may be related to the composition of memory T cell pools in non-immunologically naïve individuals. In support of this hypothesis, a study of mice infected with LCMV, VV, or vesicular stomatitis virus (VSV) prior to skin grafting found that virally induced alloreactive memory T cell activation promoted rejection and, conversely, inhibition of memory T cell promoted tolerance (Adams et al., 2003).

In cases where viral epitopes are homologous to self-antigens, cross-reactive epitopes may lead to autoimmunity. Transgenic mice expressing LCMV antigens peripherally infected with LCMV develop chronic central nervous system (CNS) inflammation despite rapid clearance of the virus and no evidence of direct viral invasion of the CNS (Evans et al., 1996). Rechallenge with LCMV or other unrelated viruses (VV and PV) leads to exacerbated CNS pathology characterized by demyelinating lesions and loss of motor function (Adams et al., 2003).

Polarized immune responses

Type 1 immune responses are characterized by the secretion of IL-12, IFN-γ and TNF-α, which enhance macrophage microbicidal activity, induce IgG2 antibodies in mice that mediate phagocytosis, and activate cytotoxic CD8 T cells. Type 2 immune responses stimulate the production of IgG1 antibodies in mice and the proliferation of mast cells and eosinophils and the secretion of IL-4, IL-5, IL-10, IL-13 and TGF-β. Certain pathogens, such as mycobacteria, elicit type 1 immune responses leading to effective containment of the organism, while others, such as helminths, predominantly induce type 2 immune responses. Both mycobacterial and helminthic infections are globally prevalent pathogens. Studies of the potential systemic effect of infections that strongly polarize the immune response on the outcome of subsequent infections have generated interesting questions. In contrast to studies of cross-reactive T cells, investigations of polarized immune responses have focused on the effect of active or chronic infection, rather than a history of prior, resolved infection.

Strongly polarizing infections may establish an immunologic milieu that suppresses or amplifies appropriate responses to infection with a second pathogen (Fig. 1, II). For example, mice infected with the murine nematode Heligmosomoides polygyrus prior to infection with Helicobacter felis have a substantial reduction in gastric expression of cytokines associated with type 1 immune responses such as IFN-γ, TNF-α and IL1-β and higher expression of IL4, IL10 and TGF-β (Fox et al., 2000). These changes in cytokine profile are associated with attenuation of gastric atrophy, a premalignant lesion caused by Helicobacter colonization. In contrast, infection with Toxoplasma gondii prior to infection with H. felis enhances type 1 immune responses and potentiates gastric inflammation, atrophy and metaplastic changes (Stoicov et al., 2004). When mice are infected with H. felis before T. gondii inoculation, blunted serum IFN-γ responses are associated with uncontrolled tachyzoite replication, severe organ damage and high mortality (Stoicov et al., 2004). These examples demonstrate that the suppression or enhancement of systemic immune responses by concurrent infection may have either beneficial or deleterious effects, depending on the predominant pathogenic mechanisms of individual pathogens.

Studies of malaria in rodents have also shown dichotomous outcomes depending on pre-existing co-infections. Although an early type 1 immune response is essential for controlling murine malaria, unregulated responses lead to immunopathology, such as cerebral malaria. Mycobacterial infections potentiate systemic type 1 responses against Plasmodium yoelii 17XL (Page et al., 2005) and protect against non-cerebral, lethal malaria (Bazaz-Malik, 1973; Clark et al., 1976), while Plasmodium infection during the chronic phase of murine tuberculosis compromises mycobacterial containment in mice (Scott et al., 2004). Helminthic infections, which enhance type 2 immune responses, exacerbate the course of P. yoelii 17XNL and Plasmodium chaubaudi (Graham et al., 2005; Noland et al., 2005). However, induction of type 2 immune responses by filaria protects mice against the development of cerebral malaria after infection with Plasmodium berghei (Yan et al., 1997). The different outcomes in non-cerebral and cerebral models of murine malaria highlight the tenuous balance between protective and deleterious immune responses in malaria pathogenesis.

The polarizing effect of heterologous infections appears to be driven by the systemic cytokine environment elicited by active infection, which may modulate subsequent cellular responses. Prior infection of mice with Mycobacterium bovis-bacille Calmette-Guerin (BCG) induces IFN-γ and reduces IL-5 and lung eosinophilia during subsequent Cryptococcus neoformans infection (Walzl et al., 2003). Protection depends on the presence of live bacteria and cannot be achieved by splenocyte transfer from M. bovis BCG-immune mice. In a study showing Schistosoma mansoni-induced protection against helminthic infection with Trichuris muris, enhanced type 2 responses in co-infected animals were detected in organs distal from the site of egg deposition (Curry et al., 1995). However, the ability to compartmentalize specific immune responses allows simultaneous type 1 and type 2 responses to occur in the same host. For example, in a model of thoracic filarial and foot pad Leishmania major co-infection, local and systemic type 2 immune responses elicited by filaria were unaffected by L. major (Lamb et al., 2005). Interestingly, co-infected animals showed enhanced type 1 responses against L. major and diminished pathology, suggesting the prior infection with filaria may prime the appropriate immune response against L. major instead of altering the type 1/type 2 balance. Therefore, although some strongly polarizing infections may influence the immune response to a second infection, the overall effect may depend on the viability of the infecting organism and the ability of the immune system to compartmentalize antigen specific responses.

Regulatory T cells

The immune system has developed several mechanisms to regulate excessive immune responses that may cause pathology and autoimmune disease. Deletion of autoreactive cells during B and T cell development leads to tolerance to most self-antigens. In addition, pathogenic immune responses may be suppressed by a specific type of CD4 T cells known as regulatory T cells (Treg). Two distinct populations of Treg cells have been described: naturally occurring Treg cells that develop in the thymus, and IL-10-secreting or adaptive Treg cells that are induced by antigenic stimulation (Bluestone and Abbas, 2003). Naturally occurring Treg cells express CD4 and CD25 and require the transcription factor Foxp3 for the lineage commitment. Adaptive Treg cells are thought to be induced by infectious challenge, have variable expression of CD25, and secrete the immunosuppressive cytokines IL-10 and TGF-β, inhibiting APC and T cell function (Fig. 1, II). Foxp3 may play a role in regulating the response of inducible Treg cells to chronic infection, but its role in non-naturally occurring Treg cells has not been fully elucidated (Fontenot and Rudensky, 2005).

Natural Treg cells appear to play a role in regulating chronic infections, such as schistosomiasis, HIV and Hepatitis C (Belkaid and Rouse, 2005). IL-10-secreting Treg cells have been implicated in the regulation of immune responses elicited by viruses (Iwashiro et al., 2001), bacteria (McGuirk et al., 2002), protozoa (Belkaid et al., 2002; Hisaeda et al., 2004) and helminths (Maizels et al., 2004). Several factors influence the induction of Treg cells, including the type and strength of the antigenic stimulation, and, importantly, the route of administration (O’Garra and Vieira, 2004). For example, mucosal antigenic exposure appears to be particularly effective in the generation of tolerance (Chen et al., 1994). In some cases, regulatory immune responses downregulate pathogenic responses, while in other instances they enhance pathogen survival and lead to chronic infection.

Although Treg cells have not been extensively evaluated in co-infection models, it appears that induction of Treg cells by one pathogen can lead to suppression of bystander responses. For example, murine infection with the gut nematode Helimosomoides polygyrus stimulates Treg cells and inhibits lymphoproliferative responses (Telford et al., 1998; Maizels et al., 2004). H. polygyrus-infected mice are unable to control Nippostrongylus brasiliensis infection and develop a chronic infection compared with the short-lived infection in mice infected only with N. brasiliensis (Colwell and Wescott, 1973). H. polygyrus infection leads to decreased gastric atrophy and higher expression of IL-10 and TGF-β in mice co-infected with H. felis, suggesting that adaptive Treg cells may be playing a protective role (Fox et al., 2000). In a murine model of inflammatory bowel disease, Helicobacter hepaticus infection induces IL-10-secreting Treg cells that are protective against bacteria-induced colitis (Kullberg et al., 2002). The majority of the Treg cells in this system are CD4+CD25–, suggesting that adaptive Treg cells play a more prominent role than natural Treg cells. In brief, Treg cells modulate pathogenic and protective immune responses to infection in the host may be important mediators that influence the outcome of co-infections.

Priming innate responses

The activation of innate immune pathways by one pathogen can modulate immune responses to subsequent infection with another pathogen. The innate immune system provides the first line of defence against infection through the activation of macrophages, dendritic cells and natural killer (NK) cells. Highly conserved receptors on APCs known as pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns and allow the immune system to distinguish self from non-self molecules. Activation of PRRs such as Toll-like receptors (TLRs) leads to a cascade of inflammatory responses and, ultimately, the secretion of cytokines and chemokines.

These innate responses play an important role in the initiation and development of subsequent adaptive responses. In response to specific microbial exposure, dendritic cells influence the development of naïve T cells into polarized Th1, Th2 or Treg cells (de Jong et al., 2002; McGuirk et al., 2002). Stimulation of TLRs may influence the activation of antigen-specific immune responses through the upregulation of cytokines and receptors that regulate adaptive responses (Fearon and Locksley, 1996). TLR signalling appears to be essential for the induction of type 1 responses as MyD88-deficient mice, which have an impaired ability to signal through TLRs, mount impaired type 1 but normal type 2 immune responses (Schnare et al., 2001).

Ongoing infections may serve as adjuvants for subsequent infections through the induction of co-stimulatory molecules and receptors that enhance APC function and recruitment (Fig. 1, I). An influx of NK cells and macrophages to the liver is seen in hepatitis B virus transgenic mice co-infected with P. yoelii (Pasquetto et al., 2000). Enhanced hepatitis B viral clearance in mice co-infected with P. yoelii (Pasquetto et al., 2000) or LCMV (Guidotti et al., 1996) is associated with activation of Kupffer cells, recruitment of NK cells and T cells, and high production of TNF-α, IFN-γ and IFNα/β. Likewise, modified heat-labile toxin from Escherichia coli enhances immunity to a variety of pathogens including respiratory syncytial virus (RSV), influenza virus and C. neoformans by recruiting activated APCs to the lung (Williams et al., 2004). Adoptive transfer of isolated alveolar monocytes from mice pretreated with toxin protects against subsequent influenza virus infection, suggesting that protection is independent of T and B cells (Williams et al., 2004). It appears that activation of APCs by one pathogen primes the innate response against a second pathogen.

In some instances, encounter with activated APCs may be deleterious. For example, activation of innate responses by various pathogens has been shown to increase HIV replication and may lead to faster progression of HIV in co-infected individuals. Enhancement of HIV replication is related in part to the activity of cellular transcription factors such as nuclear factor-κB (NF-κB). In addition to playing a crucial role in immune activation, NF-κB binds to the HIV enhancer region of the long-terminal repeat (LTR) and induces HIV gene expression (Roulston et al., 1995). Several infections have been shown to increase HIV replication through NF-κB-mediated signalling. Cultures of human tonsillar tissue infected ex vivo with HIV and Leishmania infantum show that Leishmania-induced HIV replication is related to TNF-α and IL-1α production (Zhao et al., 2004). Leishmania donovani and its surface molecule, lipophosphoglycan (LPG), activate HIV replication in monocytoid cells and in CD4 T cells through the induction of NF-κB-binding elements (Bernier et al., 1995; 1998a). Similarly, the cell wall component mannose-capped lipoarabinomannan (ManLAM) of Mycobacterium tuberculosis (Bernier et al., 1998b), and hepatitis B virus antigens induce HIV replication in an NF-κB-dependent manner (Gomez-Gonzalo et al., 2001).

Stimulation of TLRs by co-infecting pathogens may also lead to enhanced HIV replication through similar mechanisms (Bafica et al., 2004). In vitro, TLR2 stimulation by Staphylococcus epidermidis or M. tuberculosis leads to HIV-long terminal repeat trans-activation (Equils et al., 2003). Co-stimulation with TLR4 and TLR2 or TLR9 ligands induces the synergistic release of IFN-γ and TNF-α, and enhances HIV replication (Equils et al., 2003). In an HIV-transgenic mouse model, TLR2 is required for the induction of HIV by M. tuberculosis and Mycobacterium avium (Bafica et al., 2003). These findings suggest that infections commonly found in HIV-infected patients may promote HIV virus replication in the host.

Heterologous immunity in humans

  1. Top of page
  2. Summary
  3. Introduction
  4. Animal models of heterologous immunity
  5. Heterologous immunity in humans
  6. Therapeutic implications and future research
  7. References

Cross-reactive T cells

Examples of cross-reactive epitopes exacerbating disease in humans can be found when viruses of different serotypes sequentially infect a host. For instance, the pathogenesis of dengue haemorrhagic fever (DHF) is thought to be mediated by cross-reactive T cells to different dengue virus serotypes, which exacerbate pathogenic immune responses (Sangkawibha et al., 1984; Mathew et al., 1998; Guzman et al., 2000; Mongkolsapaya et al., 2003). There is clinical evidence that, as with dengue virus serotypes, T cell cross-reactivity elicited by completely unrelated pathogens may also influence the outcome of disease. For example, T cells that react to epitopes common to influenza A virus and hepatitis C virus (HCV) influence the outcome of HCV infection. A subset of healthy, non-HCV-infected blood donors have HCV NS3-specific memory T cells that recognize a determinant of the neuraminidase protein of influenza A virus, suggesting that exposure to influenza may lead to anti-HCV memory responses in HCV-uninfected individuals (Wedemeyer et al., 2001). Interestingly, patients who develop severe acute HCV infection have unusually strong CD8 T cell responses to the HCV NS3 epitope, which cross-reacts with the influenza virus neuraminidase sequence (Urbani et al., 2005). These findings suggest that exposure to influenza leads to CD8 T cell cross-reactivity, which influences the severity of HCV-associated liver pathology during acute infection. This is consistent with the evidence from murine models showing that expansion of pre-existing cross-reactive memory CD8 T cells can modify the primary immune response and modulate the immunopathologic response to subsequent infection (Fig. 1, III).

Polarized immune responses

In general, polarized immune responses are more clearly demarcated in inbred mice than in people (Mestas and Hughes, 2004), but there are several clinical examples of human pathogens that induce polarized immune responses. For instance, patients co-infected with shistosomiasis and HCV predominantly mount type 2 immune responses and have weak HCV-specific CD4 responses compared with patients infected with HCV alone (Kamal et al., 2001a,b). These findings are associated with higher HCV viral loads and lower viral clearance, which may explain the higher incidence of cirrhosis and hepatocellular carcinoma in co-infected patients compared with those infected with HCV alone (Angelico et al., 1997; Kamal et al., 2000; 2001b).

Infection with schistosomiasis may also influence the immune response to HIV. S. mansoni co-infected adults have decreased Gag-specific CD8+ cytolytic T cell responses and increased number of Gag-specific IL-10 positive CD8+ T cells (McElroy et al., 2005). Given the deleterious effect of type 2 responses on HIV pathogenesis, it has been suggested that therapy against helminthic infections and schistosomiasis may slow HIV progression (Fincham et al., 2003). However, a recent study from Uganda showed that treatment of S. mansoni was associated with transient increases in viral load and sustained decreases in CD4+ T lymphocyte count, which were associated with enhanced post-treatment S. mansoni-specific type 2 responses (Brown et al., 2005).

Interestingly, the ability to mount polarized immune responses may be partly determined in utero. A cross-sectional study of mother–child pairs in Kenya showed that prenatal sensitization to filariae and schistosomes occurs in ∼50% of newborns and is relatively long-lasting, persisting into childhood (Malhotra et al., 1999). BCG-vaccinated children born to mothers without filariasis or schistosomiasis produced 10 times more IFN-γ in response to mycobacterial antigens than BCG-vaccinated children of helminth-infected mothers (Malhotra et al., 1999). These data suggest that prenatal sensitization can bias immunity induced by M. bovis BCG away from protective type 1 immune responses. In adults, helminthic infections are also associated with blunted IFN-γ responses to tuberculin antigen (Ferreira et al., 2002).

These findings may have implications for vaccination strategies. The efficacy of M. bovis BCG against tuberculosis correlates with distance from the equator; greater protection has been observed at higher latitudes (Palmer and Long, 1966; Fine, 1995). Higher exposure to environmental bacteria commonly found in warm climates is thought to influence subsequent responses to BCG (Fine, 1995). Similarly, helminthic infections are more prevalent in tropical climates and may downregulate effective cell-mediated immune responses to mycobacteria (Malhotra et al., 1999; Ferreira et al., 2002). Treatment of intestinal parasites prior to BCG vaccination is associated with improved proliferation and IFN-γ production by peripheral blood mononuclear cells after stimulation with tuberculin antigens (Elias et al., 2001). However, the effect of antihelminthic therapy during pregnancy and prior to immunization on the actual efficacy of BCG vaccine has not been established.

Polarization of immune responses by vaccination may influence the outcome of future infections. Epidemiologic studies have shown that immunization with live attenuated vaccines that elicit predominantly type 1 immune responses, such as M. bovis BCG and measles vaccine had a non-specific beneficial effect on childhood survival. In contrast, diphtheria-pertussis-toxoid (DPT) vaccine, which primarily elicits type 2 immune responses, had the opposite effect (Kristensen et al., 2000; Garly et al., 2003; Shann, 2004; Roth et al., 2005). Despite controlling for the vaccine preventable infections, it was difficult to prove a true causal relationship between vaccination and survival because the specific cause of death in most of the children was not well established in these studies. However, it is tempting to speculate that the persistent immunomodulatory properties of these vaccines may impact host susceptibility to infections. Type 1-polarized immune responses may be effective against many childhood pathogens commonly encountered in the developing world (Shann, 2004).

The effect of systemic polarized responses elicited by chronic infections may have implications beyond the field of infectious diseases. In particular, the ‘hygiene hypothesis’ argues that the dramatic rise in atopic disorders observed in industrialized countries over the last few decades may be related to a decline in infectious diseases resulting from improved living standards and immunization programmes (Strachan, 1989; Yazdanbakhsh et al., 2002). The relative paucity of allergic diseases in developing countries supports this concept. Susceptibility to allergic diseases may result from a combination of genetic and environmental factors. For example, it has been demonstrated that Hepatitis A virus may protect against atopy in individuals who carry a particular variant of the gene that encodes TIM-1, a glycoprotein that co-stimulates T cell activation and has been implicated in atopic diseases (McIntire et al., 2003). It has been proposed that TIM-1, which is a receptor for hepatitis A, facilitates entry in to TIM-1 cells, leading to deletion of Th2 cells and a reduction in asthma.

Other pathogens, such as mycobacteria (Shirakawa et al., 1997), measles (Shaheen et al., 1996) and gastrointestinal organisms (Matricardi et al., 2000) have been inversely correlated with atopic responses. Immune profiles of individuals with positive tuberculin skin tests show a type 1 cytokine predominance and lower IgE serum levels (Shirakawa et al., 1997). Paradoxically, helminthic infections, which induce strong type 2 immune responses, also protect against allergic disease (Lynch et al., 1987; van den Biggelaar et al., 2004). It has been proposed that persistent immune challenge from chronic infectious pathogens, such as helminths and mycobacteria, induce an anti-inflammatory regulatory network that protects against allergic diseases (Mahanty and Nutman, 1995; Yazdanbakhsh et al., 2002).

Regulatory T cells

There is mounting evidence that chronic infections induce Treg cells that can modulate the response to bystander antigenic stimulation. In addition to protecting against allergic disease (Lynch et al., 1987; van den Biggelaar et al., 2004), heavy parasitic infections can attenuate antigen-specific T cell responses. For example, individuals infected with Onchocerca volvulus have diminished antibody production, proliferative responses and IFN-γ production following vaccination with tetanus toxoid compared with uninfected vaccinated controls (Cooper et al., 1998). Furthermore, O. volvulus-infected individuals produced significantly higher levels of IL-10 compared with uninfected controls, suggesting that Treg-mediated pathways may play an immunosuppressive role. Likewise, asymptomatic patients infected with Wucheria bancrofti mount lower proliferative and IFN-γ responses after vaccination with tetanus toxoid compared with uninfected individuals (Nookala et al., 2004). Diminished immune responses appear to be mediated by IL-10, which is secreted at higher levels in peripheral blood mononuclear cells (PBMCs) from microfilaremic patients compared with controls. Although none of these studies directly evaluate the role of Treg cells, the association between helminthic infections and anti-inflammatory cytokines such as IL-10 suggests that regulatory immunosuppressive mechanisms may be playing a role in the diminished immune response to concurrent infections.

Priming innate responses

As predicted by experimental data showing enhanced HIV replication in co-infection models, opportunistic infections can accelerate the clinical progression of HIV (Perneger et al., 1995; Whalen et al., 1995). For example, infection with M. tuberculosis leads to higher HIV viral loads and faster CD4 declines (Toossi et al., 1993; Goletti et al., 1996). In general, activation of T cells, macrophages and dendritic cells is thought to enhance viral entry and promote HIV replication. Bronchoscopic samples obtained from patients co-infected with M. tuberculosis and HIV show that changes in CXCR4 expression patterns may contribute to the accelerated progression of HIV with tuberculosis. HIV strains that use the CXCR4 co-receptor (X4 strains) instead of the CCR5 co-receptor (R5 strains) for entry into T cells are associated with a more rapid decline in CD4 cells. CXCR4 expression on alveolar macrophages obtained by bronchoscopic lavage is significantly higher in patients co-infected with M. tuberculosis and HIV than in HIV-infected patients without tuberculosis (Hoshino et al., 2004). In vitro, M. tuberculosis infection of macrophages increases CXCR4 expression and entry of X4 virus (Hoshino et al., 2004), suggesting that the innate response to M. tuberculosis may favour X4 viral replication. The effect of latent tuberculosis infection on HIV progression has not been well characterized, though the implications could be important as it is estimated that one-third of the world's population is latently infected (Dye et al., 1999).

Several epidemiological studies have shown that active HSV-2 infection is associated with an increased risk of HIV acquisition (Boulos et al., 1992; Hook et al., 1992; Corey et al., 2004). Although mechanical disruption of mucous membranes is the major risk factor for increased HIV acquisition, local recruitment and activation of CD4 T cells (Cunningham et al., 1985) and macrophages (Kucera et al., 1990; Heng et al., 1994) increase the number of target cells for HIV entry. HSV promotes HIV replication in human T cells (Mosca et al., 1987) and in macrophages by inducing NF-κB activity (Moriuchi et al., 2000). Increased HIV viral shedding can also be found in subclinical non-ulcerative HSV (Mbopi Keou et al., 1999; McClelland et al., 2002) suggesting that HIV transmissibility may be enhanced without direct mucosal disruption and herpetic ulceration. Ongoing clinical trials are evaluating the role of acyclovir in reducing HIV transmission.

Therapeutic implications and future research

  1. Top of page
  2. Summary
  3. Introduction
  4. Animal models of heterologous immunity
  5. Heterologous immunity in humans
  6. Therapeutic implications and future research
  7. References

Accumulating experimental and clinical evidence supports the concept that prior infections or concurrent active infections can modify the response to unrelated pathogens. Animal models have been essential in establishing the biologic plausibility of epidemiological studies, which have implicated heterologous immune responses in host susceptibility to infectious disease, organ transplantation rejection and autoimmune disease. In particular, these models have elucidated important mechanisms associated with heterologous immune responses, such as the role of cross-reactive T cells, and signalling environments that prime the innate immune system, and regulate or polarize immune responses. Depending on the particular infection, these mechanisms can be protective or exacerbate immunopathology (Fig. 1). Further elucidation of the instructive effect of innate responses on the adaptive immune response, and the role of regulatory pathways induced with chronic infections may provide further insights on the development of heterologous immune responses.

The immunomodulatory effect of infectious pathogens may have important therapeutic implications. Studies that address whether the associations between co-infecting pathogens and disease outcomes are causally related could be tested by implementing specific interventions that impact the outcome of disease. Some pathogens commonly diagnosed in co-infected individuals are amenable to treatment. For example, the rapid progression of HCV in individuals co-infected with schistosomiasis (Angelico et al., 1997; Kamal et al., 2000; 2001a,b) may be delayed with schistosomiasis therapy. Likewise, primary prophylaxis against opportunistic infections and treatment of other co-infections may slow the progression of HIV (Boulos et al., 1992; Hook et al., 1992; Toossi et al., 1993; Perneger et al., 1995; Whalen et al., 1995; Goletti et al., 1996; Corey et al., 2004). Other potential areas of research include the effect of antihelminthic therapy for pregnant women and children on the efficacy of routine vaccines (Malhotra et al., 1999; Elias et al., 2001; Ferreira et al., 2002), and the impact of pre-emptive antiviral therapy on the development of graft tolerance in transplant recipients (Flamand et al., 1993; Aalto et al., 1998; Burak et al., 2002; Singh et al., 2002; Singh, 2005). However, the unexpected deleterious effect of S. mansoni therapy on HIV progression highlights the importance of conducting clinical trials to test these hypotheses (Brown et al., 2005). Carefully controlled trials are needed to correlate experimental findings to disease outcomes in humans and to evaluate clinical responses to potential intervention strategies.


  1. Top of page
  2. Summary
  3. Introduction
  4. Animal models of heterologous immunity
  5. Heterologous immunity in humans
  6. Therapeutic implications and future research
  7. References
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