Pre-existing Simian Immunodeficiency Virus Infection Increases Expression of T Cell Markers Associated with Activation during EarlyMycobacterium tuberculosisCoinfection and Impairs TNF Responses in Granulomas

Abstract

Tuberculosis (TB) is the leading infectious cause of death among people living with HIV. People living with HIV are more susceptible to contracting Mycobacterium tuberculosis and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on M. tuberculosis coinfection is critical in combating this global health epidemic. We previously showed in a model of SIV and M. tuberculosis coinfection in Mauritian cynomolgus macaques (MCM) that SIV/M. tuberculosis–coinfected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to M. tuberculosis infection. We infected MCM with SIVmac239, followed by coinfection with M. tuberculosis Erdman 6 mo later. Although similar, TB progression was observed in both SIV+ and SIV-naive animals at 6 wk post–M. tuberculosis infection; longitudinal sampling of the blood (PBMC) and airways (bronchoalveolar lavage) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways of SIV+ animals. At sites of M. tuberculosis infection (i.e., granulomas), SIV/M. tuberculosis–coinfected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ T cells in granulomas of SIV/M. tuberculosis–coinfected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of M. tuberculosis replication soon postinfection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection, which promotes TB progression.

Spontaneous Control of SIV Replication Does Not Prevent T Cell Dysregulation and Bacterial Dissemination in Animals Co-Infected with M. tuberculosis

“…S1A) or the extent of gross pathology as measured by necropsy scores (data not shown). The clinical outcomes and more comprehensive T cell analyses of this study are further described in Larson et al ( 15 ) and Ellis et al ( 16 ). Animals were necropsied 6 weeks after Mtb infection to characterize the association of the extent of SIV replication with antimycobacterial T cell responses in tissues prior to the development of severe TB pathology (e.g., TB pneumonia) ( 10 ).…”

“…For this analysis, we used samples derived from a previously reported animal study ( 15 , 16 ). One cohort of 8 M1+ MCM was infected with SIVmac239 for 6 months, followed by co-infection with a low dose (3 to 19 CFU) of a molecularly barcoded Mtb Erdman strain for 6 weeks ( Fig.…”

“…1A ). A second cohort of 8 SIV-naive MCM were infected with the same strain and dose of Mtb for 6 weeks ( 15 , 16 ). There were no significant differences in CFU dose between cohorts (Fig.…”

“…These results implied that collecting granulomas at 6 weeks after infection with Mtb may provide a snapshot of the extent of local SIV and Mtb burden, as well as the corresponding T cell response, prior to the development of pathological TB disease. As a result, we subsequently explored TB disease in SIV+ and SIV-naive MCMs who were euthanized at 6 weeks post-Mtb infection ( 15 ), and we found that SIV+ animals had a lower CD4:CD8 ratio and increased immune activation in the Mtb-affected tissues when compared to those who were SIV-naive. In that study, however, we did not explore whether the control of SIV replication was related to (i) the extent of Mtb replication or dissemination or (ii) the frequency of CD4 + and CD8 + T cells producing cytokines in the granulomas.…”

The relationship between previous pulmonary tuberculosis and risk of lung cancer in the future

“…Multiple lines of evidence displayed that tuberculosis infection is accompanied by increased expression of immune inhibitory receptors in immune cells, such as NK cell and T cell. M. tuberculosis/ Simian immunodeficiency virus (SIV)–coinfected animals had a higher frequency T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and PD-1 expression in CD4 + and CD8 + T cells [ 99 ]. TIGIT is an inhibitory receptor, which exerts a crucial role in limiting innate and adaptive immunity.…”