Modulatory effects of helminth coinfection on host immune responses to Mycobacterium tuberculosis : examining potential outcomes

Parasitic worm infections, helminths, and Mycobacterium tuberculosis (Mtb) coinfections are common in regions where both infections are endemic, yet their interactions and impact on host immunity against Mtb remain complex and species-dependent. Mtb is the etiological agent of tuberculosis (TB), which is the leading cause of death from a single infectious agent worldwide. Approximately one-quarter of the world’s population is infected with Mtb and has latent TB infection without showing symptoms. About 5-10% of these will develop active TB at some point in their lives, depending on certain risk factors, comorbidities, or coinfections. Treating TB is challenging due to the emergence of drug-resistant strains, the lengthy treatment duration, significant side effects, and complications arising from coinfections like HIV and helminths. Helminths, known to induce a Th2-biased immune response, may influence the control of Mtb, which relies on a robust Th1 response. In this series of studies, we explored the effects of helminth antigen exposure on innate and adaptive immune responses during Mtb infection. Using antigens from Ascaris lumbricoides (ASC) and Schistosoma mansoni (SM), we demonstrated that helminth antigen-exposure directly influences the early immune control of Mtb in monocytes and macrophages, promoting enhanced bacterial control without classical Th1/Th2 cytokine involvement. Our findings showed that exposure to SM helminth antigen reduced Mtb growth in monocytes. Furthermore, pre-exposure with ASC antigen during monocyte-to-macrophage differentiation, or of mature macrophages, also reduced Mtb growth. This in vitro model demonstrates that helminth infection can enhance early control and killing of Mtb by directly stimulating phagocytic cells, highlighting the potential role of helminth antigens in modulating the monocyte-macrophage axis even without involvement of cell-mediated immunity. Further investigation revealed that ASC helminth antigen-exposed macrophages released extracellular vesicles (EVs) that decreased Mtb-induced IL-1β and enhanced bacterial growth control of Mtb in treatment naïve human monocyte-derived macrophages (hMDMs). These EVs contained specific microRNAs with the capacity to attenuate proinflammatory responses through regulation of signaling pathways, such as MAPK and PI3K-AKT. In contrast, SM helminth antigen exposure generated EVs containing microRNAs that modulated TGF-β signaling, highlighting distinct immune regulatory mechanisms. Additionally, helminth exposure in a T and B cell co-culture systems induced a B cell-associated decreased T cell proliferation regardless of helminth antigen presence. Notably, soluble IL-15Rα levels increased in co-culture supernatants only with ASC helminth exposure. IL-15Rα was also elevated on CD4 T cells in these co-cultures. Restimulation with recombinant human IL-15 (rhIL-15) resulted in lower and transient STAT5 activation in CD4 and CD8 T cells within the ASC group compared to co-cultures without ASC exposure. Despite diminished IL-15 signaling in the ASC group, all groups maintained the Th1 marker CD183. B cells in ASC helminth-exposed co-cultures restimulated with rhIL-15 exhibited reduced BCL6 expression with maintained BLIMP-1 transcription factor expression. Lastly, in a cohort of helminth/TB coinfected patients, plasma samples from smear-positive TB patients were analyzed to assess total and Mtb-specific antibody responses. Utilizing a novel enzyme-linked immunosorbent assay (ELISA) approach, plates were coated with a cell-membrane fraction of Mtb strain CDC1551, which includes a broad spectrum of Mtb surface proteins. Patients coinfected with helminths and TB exhibited significantly elevated levels of Mtb-specific IgG (involving an IgG1 and IgG2 subclass response) and IgM compared to controls without helminth or TB infection. These elevated antibody levels were also observed in TB patients without helminth infection, although this group further showed elevated levels of Mtb-specific IgA previously linked to the extent or severity of infection. This study indicates that there is a robust antibody response in TB patients irrespective of helminth coinfection. Altogether, these findings highlight the complex interactions between helminth infections and Mtb, emphasizing the need for further studies on the species-specific effects of helminths. Such research could have significant implications for TB vaccine development and therapeutic strategies that target both innate and adaptive immune responses.