Humans are colonized by complex, site-specific microbial communities that are increasingly implicated in human health and disease in unexpected ways. In some cases, microbial communities are thought to modulate non-infectious diseases, such as obesity 
, asthma and autoimmune diseases 
. Viewed broadly, the human microbiota may be a major regulator of the immune system modulating not only inflammatory disorders (the “hygiene hypothesis”), but responses to infectious challenges as well 
. Because they continuously stimulate non-specific responses in the host, chronic mucosal infections may be particularly important in this regard.
The high prevalence of H. pylori in populations where TB and other lethal infections remain endemic suggests the host-pathogen interplay of these infections has co-evolved. In this report, we have presented evidence from three different study designs that H. pylori infection affects response to M. tuberculosis. First, we found in a cross-sectional human study that H. pylori is associated with enhanced IFN-γ and Th1-like responses to specific TB antigens. Second, in baseline samples from two high risk human tuberculosis case-contact cohorts, we observed that infected household contacts who maintain latency over two years are significantly more likely to have concurrent H. pylori infection than are TB cases, although seroprevalence was not different in incident TB cases. Finally, in a retrospective cohort study of low-dose M. tuberculosis challenge monkeys, we observed that H. pylori-infected animals are significantly less likely to develop active disease than are uninfected animals. While further studies are indicated, taken together, these lines of investigation offer a heretofore unexplored role for infections like H. pylori to alter the outcome of M. tuberculosis infection.
We propose two potential models by which H. pylori
could promote a protective immune response to TB infection. In the first model, an infection in early childhood could permanently differentiate immature T-cells to a Th1-like phenotype. Such a “hygiene hypothesis,” has been advanced for hepatitis A 
, and would favor past as well as ongoing infections contributing to a state of heightened immunity. Alternatively, H. pylori
might induce a bystander effect with continuous inflammation and T-cell signaling enhancing the host's innate response to a spectrum of infectious challenges. Similar effects have been demonstrated with γ-herpesvirus in mice challenged with Listeria monocytogenes
and Yersinia pestis 
. These authors speculate that non- specific induction of interferon-γ (IFN-γ) activates macrophages and primes innate defenses to other infections. We did not test for antibodies to HAV or herpesviridae in the human tuberculosis case-contact cohorts. Because these exposures are likely to be very common in populations where both H. pylori
and M. tuberculosis
infections are common, more systematic sampling designs may be needed to adequately explore interaction effects.
naturally infects macaques. The fact that we were able to replicate a significant association of H. pylori
infection with latent outcomes in the Pittsburgh cynomolgus monkey TB challenge model 
offers new opportunities to explore mechanistic arguments in depth. Because the present work is based on a convenience sample from the Pittsburgh laboratory, repeated measures of immunologic responses and clinical progression were not investigated. More systematic experimental study designs, including prospective studies utilizing H. pylori
challenge, are planned.
The accuracy of H. pylori
serology in the developing world is suboptimal 
. Although the CagA assay may be more reliable for comparing different populations, misclassification of H. pylori
infection status still cannot be excluded. Typically, misclassification tends to yield a null result unless, for some reason, cases and controls respond differently to the assay. We speculated that TB cases might have weakened antibody responses, causing us to have a spurious result. However, the fact that measles antibody titers were robust and virtually the same in Gambian TB cases and age and sex-matched latently infected contacts argues against this explanation of results. That H. pylori
seroprevalence did not differ between incident TB cases and nonprogressors in our cohort samples, while limiting our conclusions, can also reflect artifacts of the TBCC study model, including the low numbers of secondary cases, ascertainment differences or biases, as well as limitations of H. pylori
serologic detection in this setting. In both cohorts, most cases of TB were identified at an initial screening visit, and M. tuberculosis
infection at baseline was a relatively weak predictor of progression 
. Thus, continued work with longitudinal cohorts may benefit from multi-site study designs incorporating additional H. pylori
diagnostics as well as other prognostic biomarkers of immune response to TB exposure and infection.
specific antigen interferon-γ release assays are important noninvasive tools for measuring immunogenicity of the heterologous prime boost T-cell based vaccines for TB 
. Our results raise the possibility that H. pylori
infection and other Th-1 modifying infections present in the host background can alter these profiles. As our results also do not exclude the possibility that M. tuberculosis
modifies the host response to H. pylori
infection, PBMC responses to TB antigens pre- and post- antibiotic treatment for H. pylori
would help shed light on the specificity of our findings, including reversibility. In vitro
studies examining possible mechanisms of T-cell cross reactivity, such as effect of H. pylori
antigen on M. tuberculosis
antigen presenting cells and MHC expression, are also needed.
Why only 10% of infected individuals succumb to tuberculosis remains one of the most vexing public health questions–one which the one-pathogen-one-disease paradigm is ill-equipped to answer. While preliminary, our work suggests that one factor contributing to the clinical outcome of TB infection may be a concurrent chronic infection. The hypothesis that the human microbiome has evolved to provide context-specific competitive risk advantages to the host 
also raises the intriguing possibility that our microbiota can be manipulated to modulate disease risk from M. tuberculosis
, as well as other common human pathogens