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CD4 T Cells in Mycobacterium tuberculosis and Schistosoma mansoni Co-infected Individuals Maintain Functional TH1 Responses.

ABSTRACT: Mycobacterium tuberculosis (Mtb) is a serious public health concern, infecting a quarter of the world and leading to 10 million cases of tuberculosis (TB) disease and 1. 5 million deaths annually. An effective type 1 CD4 T cell (TH1) immune response is necessary to control Mtb infection and defining factors that modulate Mtb-specific TH1 immunity is important to better define immune correlates of protection in Mtb infection. Helminths stimulate type 2 (TH2) immune responses, which antagonize TH1 cells. As such, we sought to evaluate whether co-infection with the parasitic helminth Schistosoma mansoni (SM) modifies CD4 T cell lineage profiles in a cohort of HIV-uninfected adults in Kisumu, Kenya. Individuals were categorized into six groups by Mtb and SM infection status: healthy controls (HC), latent Mtb infection (LTBI) and active tuberculosis (TB), with or without concomitant SM infection. We utilized flow cytometry to evaluate the TH1/TH2 functional and phenotypic lineage state of total CD4 T cells, as well as CD4 T cells specific for the Mtb antigens CFP-10 and ESAT-6. Total CD4 T cell lineage profiles were similar between SM+ and SM- individuals in all Mtb infection groups. Furthermore, in both LTBI and TB groups, SM infection did not impair Mtb-specific TH1 cytokine production. In fact, SM+ LTBI individuals had higher frequencies of IFN?+ Mtb-specific CD4 T cells than SM- LTBI individuals. Mtb-specific CD4 T cells were characterized by expression of both classical TH1 markers, CXCR3 and T-bet, and TH2 markers, CCR4, and GATA3. The expression of these markers was similar between SM+ and SM- individuals with LTBI. However, SM+ individuals with active TB had significantly higher frequencies of GATA3+ CCR4+ TH1 cytokine+ Mtb-specific CD4 T cells, compared with SM- TB individuals. Together, these data indicate that Mtb-specific TH1 cytokine production capacity is maintained in SM-infected individuals, and that Mtb-specific TH1 cytokine+ CD4 T cells can express both TH1 and TH2 markers. In high pathogen burden settings where co-infection is common and reoccurring, plasticity of antigen-specific CD4 T cell responses may be important in preserving Mtb-specific TH1 responses.

SUBMITTER: McLaughlin TA

PROVIDER: S-EPMC7020828 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CD4 T Cells in Mycobacterium tuberculosis and Schistosoma mansoni Co-infected Individuals Maintain Functional TH1 Responses.

McLaughlin Taryn A TA Khayumbi Jeremiah J Ongalo Joshua J Tonui Joan J Campbell Angela A Allana Salim S Gurrion Ouma Samuel S Odhiambo Felix Hayara FH Gandhi Neel R NR Day Cheryl L CL

Frontiers in immunology 20200207

Mycobacterium tuberculosis (Mtb) is a serious public health concern, infecting a quarter of the world and leading to 10 million cases of tuberculosis (TB) disease and 1. 5 million deaths annually. An effective type 1 CD4 T cell (TH1) immune response is necessary to control Mtb infection and defining factors that modulate Mtb-specific TH1 immunity is important to better define immune correlates of protection in Mtb infection. Helminths stimulate type 2 (TH2) immune responses, which antagon ...[more]

PMID: 32117277

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Project description:IntroductionLittle is known about hepatotoxicity in patients with schistosome and HIV co-infections. Several studies have reported increased liver enzymes and bilirubin levels associated with schistosome infection. We investigated whether HIV-infected adults on antiretroviral therapy who had S. mansoni co-infection had a higher prevalence of hepatotoxicity than those without.Methodology/principal findingsWe determined the presence and grade of hepatotoxicity among 305 HIV-infected outpatients who had been on medium-term (3-6 months) and long-term (>36 months) antiretroviral therapy in a region of northwest Tanzania where S. mansoni is hyperendemic. We used the AIDS Clinical Trial Group definition to define mild to moderate hepatotoxicity as alanine aminotransferase, alanine aminotransferase, and/or bilirubin elevations of grade 1 or 2, and severe hepatotoxicity as any elevation of grade 3 or 4. We determined schistosome infection status using the serum circulating cathodic antigen rapid test and used logistic regression to determine factors associated with hepatotoxicity. The prevalence of mild-moderate and severe hepatotoxicity was 29.6% (45/152) and 2.0% (3/152) in patients on medium-term antiretroviral therapy and 19.6% (30/153) and 3.3% (5/153) in the patients on long-term antiretroviral therapy. S. mansoni infection was significantly associated with hepatotoxicity on univariable analysis and after controlling for other factors associated with hepatotoxicity including hepatitis B or C and anti-tuberculosis medication use (adjusted odds ratio = 3.0 [1.6-5.8], p = 0.001).Conclusions/significanceOur work demonstrates a strong association between S. mansoni infection and hepatotoxicity among HIV-infected patients on antiretroviral therapy. Our study highlights the importance of schistosome screening and treatment for patients starting antiretroviral therapy in schistosome-endemic settings. Additional studies to determine the effects of schistosome-HIV co-infections are warranted.

Project description:BackgroundIn the Sudan, Schistosoma mansoni infections are a major cause of morbidity in school-aged children and infection rates are associated with available clean water sources. During infection, immune responses pass through a Th1 followed by Th2 and Treg phases and patterns can relate to different stages of infection or immunity.MethodologyThis retrospective study evaluated immunoepidemiological aspects in 234 individuals (range 4-85 years old) from Kassala and Khartoum states in 2011. Systemic immune profiles (cytokines and immunoglobulins) and epidemiological parameters were surveyed in n = 110 persons presenting patent S. mansoni infections (egg+), n = 63 individuals positive for S. mansoni via PCR in sera but egg negative (SmPCR+) and n = 61 people who were infection-free (Sm uninf). Immunoepidemiological findings were further investigated using two binary multivariable regression analysis.Principal findingsNearly all egg+ individuals had no access to latrines and over 90% obtained water via the canal stemming from the Atbara River. With regards to age, infection and an egg+ status was linked to young and adolescent groups. In terms of immunology, S. mansoni infection per se was strongly associated with increased SEA-specific IgG4 but not IgE levels. IL-6, IL-13 and IL-10 were significantly elevated in patently-infected individuals and positively correlated with egg load. In contrast, IL-2 and IL-1β were significantly lower in SmPCR+ individuals when compared to Sm uninf and egg+ groups which was further confirmed during multivariate regression analysis.Conclusions/significanceSchistosomiasis remains an important public health problem in the Sudan with a high number of patent individuals. In addition, SmPCR diagnostics revealed another cohort of infected individuals with a unique immunological profile and provides an avenue for future studies on non-patent infection states. Future studies should investigate the downstream signalling pathways/mechanisms of IL-2 and IL-1β as potential diagnostic markers in order to distinguish patent from non-patent individuals.

Dataset Information

CD4 T Cells in Mycobacterium tuberculosis and Schistosoma mansoni Co-infected Individuals Maintain Functional TH1 Responses.

Publications

CD4 T Cells in <i>Mycobacterium tuberculosis</i> and <i>Schistosoma mansoni</i> Co-infected Individuals Maintain Functional TH1 Responses.

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