Mycobacterium tuberculosis‐specific CD4⁺ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

Abstract

In many settings, adults with active or latent tuberculosis will also be coinfected with helminths. Our study aimed to investigate how anthelmintic treatment modulates antimycobacterial immunity, in a setting where helminth reinfection should not occur. Additional supporting information may be found in the online version of this article at the publisher's web-site We investigated the potential impact of helminth infection on immune responses to Mycobacterium tuberculosis (Mtb) in patients with latent Mtb infection with or without helminth infection (Strongyloides orSchistosoma IntroductionMycobacterium tuberculosis (Mtb) infects a third of the world's population, causing 1.5 million deaths a year [1,2]. In addi- Correspondence:Frederic Toulza e-mail: Frederic.Toulza@lshtm.ac.uk tion, helminth infections are estimated to affect 1.5 billion people worldwide, with the majority of these infections concentrated in developing countries where tuberculosis (TB) is endemic [3,4]. Helminth infections are reported to induce Th2 type immune responses in the host [5], and evidence suggests that Th2 cytokines may play a critical role in reducing the Th1 immune response to other infections. Protection against TB is not well understood, but Th1 T-cell responses involving interferon gamma (IFN-γ), tumor C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 752-761 Clinical immunology 753 necrosis factor alpha (TNF-α), and interleukin 2 (IL-2) are induced in the immune response to Mtb [6]. IFN-γ is thought to play an important role in the protective immune response against TB as indicated by the susceptibility of humans with IFN-γ signaling pathway deficiencies to TB disease [7,8]. A number of studies have previously investigated the immunomodulatory effect of helminth infection on antimycobacterial immunity (reviewed in [9] [22,23] and in patients with active TB [24]. A recent study showed that in children in Gabon, the proportion of Tregs decreased with anthelmintic treatment [25].There have been only a few studies that investigated the impact of helminth infections on T-cell immunity in patients with latent TB infection. Filaria infections were shown to reduce Th1 responses in Indian patients with latent Mtb infection (LTBI), that were increased with blockage of CTLA-4 or PD-1 [26], while anthelminth treatment increased TLR2 and TLR9 expression with an associated increase in production of proinflammatory cytokines. In Indian patients with LTBI, coincident hookworm infection reduced Mtb-specific Th1 and Th17 CD4 T cells [14]. Indian pulmonary TB patients with Wucheria or Stronglyoides also showed reduced CD4 and CD8 T-cell responses to mycobacterial antigens, which could be partly blocked with anti-IL-10 neutralizing antibodies [27].In this study, we measured the impact of anthelmintic treatment on the immune response to Mtb in LTBI in a migrant cohort in London. As United Kingdom is not a helminth endemic area, reinfection is not likely in this setting. This provides a unique opport...

Anthelmintic Therapy Modifies the Systemic and Mycobacterial Antigen-Stimulated Cytokine Profile in Helminth-Latent Mycobacterium tuberculosis Coinfection

“…We have previously shown that downmodulation of TLR expression and function was partially reversible by anti-filarial treatment in filarial-LTB coinfection (21). More recently, anthelmintic treatment was shown to significantly improve the Th1 response and downregulate the regulatory T cell response in helminth-LTB coinfection (14). Our study data thus add to the literature on the modulation of immune response following treatment of helminth infection in the setting of coinfections.…”

“…Similarly, hookworm infections are known to modulate Th1 and Th17 responses in an antigen-specific manner in latent TB (13). Both S. stercoralis and schistosomes are known to enhance regulatory T cell responses, which in turn downmodulate Th1 responses in latent TB (14). Finally, S. stercoralis infection is also known to influence the systemic responses of cytokines, including type 1, type 2, and type 17 cytokines, and other proinflammatory responses in coinfected individuals (10).…”

“…This modulation is known to extend to influencing the systemic cytokine responses as well (10). This has been demonstrated for filarial infections, hookworm infections, schistosomes, and S. stercoralis infection (11)(12)(13)(14). However, very few studies have examined the effect of anthelmintic treatment on the cytokine profiles of helminth-TB coinfection (14).…”

“…This has been demonstrated for filarial infections, hookworm infections, schistosomes, and S. stercoralis infection (11)(12)(13)(14). However, very few studies have examined the effect of anthelmintic treatment on the cytokine profiles of helminth-TB coinfection (14). We therefore examined the systemic and TB antigenstimulated levels of type 1, type 2, type 17, and regulatory cytokines in LTB individuals with or without S. stercoralis coinfection and in the coinfected individual before and after treatment.…”

Helminth-Tuberculosis Co-infection: An Immunologic Perspective

“…Similarly, Strongyloides and Mtb co-infection has also been shown to be associated with significantly lower systemic levels of type 1 (IFNγ, TNFα and IL-2) and Th17 (IL-17A and IL-17F) cytokines and significantly elevated systemic levels of regulatory (IL-10 and TGFβ) and type 2 (IL-4, IL-5 and IL-13) cytokines ex vivo [75]. In addition, a study of immigrants to the United Kingdom demonstrated that helminth infections (mainly Schistosoma mansoni and S. stercoralis ) were associated with a decreased frequency of CD4 + IFNγ secreting T cells and an increased frequency of CD4 + Tregs in those with LTBI in comparison to helminth-uninfected controls [76]. Interestingly, following anthelmintic treatment, the frequency of Th1 cells increased and that of Tregs decreased, indicating that the modulation of T cell responses was helminth-mediated.…”