Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide
. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy ...against pulmonary tuberculosis, the major cause of mortality and disease transmission
. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis.
Tuberculosis (TB) is the leading infectious cause of death among people living with HIV. People living with HIV are more susceptible to contracting
and often have worsened TB disease. Understanding ...the immunologic defects caused by HIV and the consequences it has on
coinfection is critical in combating this global health epidemic. We previously showed in a model of SIV and
coinfection in Mauritian cynomolgus macaques (MCM) that SIV/
-coinfected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to
infection. We infected MCM with SIVmac239, followed by coinfection with
Erdman 6 mo later. Although similar, TB progression was observed in both SIV
and SIV-naive animals at 6 wk post-
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
infection (i.e., granulomas), SIV/
-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/
-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
replication soon postinfection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection, which promotes TB progression.
In 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic ...for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during
infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However, total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.
Tuberculosis (TB), caused by
, continues to be a major global health problem. Lung granulomas are organized structures of host immune cells that function to contain the bacteria. Cytokine expression ...is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate TB. Although the importance of proinflammatory cytokines in controlling
infection has been established, the effects of anti-inflammatory cytokines, such as IL-10, in TB are less well understood. To investigate the role of IL-10, we used an Ab to neutralize IL-10 in cynomolgus macaques during
infection. Anti-IL-10-treated nonhuman primates had similar overall disease outcomes compared with untreated control nonhuman primates, but there were immunological changes in granulomas and lymph nodes from anti-IL-10-treated animals. There was less thoracic inflammation and increased cytokine production in lung granulomas and lymph nodes from IL-10-neutralized animals at 3-4 wk postinfection compared with control animals. At 8 wk postinfection, lung granulomas from IL-10-neutralized animals had reduced cytokine production but increased fibrosis relative to control animals. Although these immunological changes did not affect the overall disease burden during the first 8 wk of infection, we paired computational modeling to explore late infection dynamics. Our findings support that early changes occurring in the absence of IL-10 may lead to better bacterial control later during infection. These unique datasets provide insight into the contribution of IL-10 to the immunological balance necessary for granulomas to control bacterial burden and disease pathology in
infection.
Non-human primates (NHP) are thought to be a good preclinical animal model for tuberculosis because they develop disease characteristics that are similar to humans. The objective of the current study ...was to determine if NHPs can also be used to reliably predict the exposure of tedizolid, sutezolid, and its biologically active metabolite sutezolid-M1 in humans. The prodrug tedizolid phosphate and sutezolid were administered orally to NHPs either once or twice daily for up to eight days. The active moieties, tedizolid, and sutezolid showed linear pharmacokinetics and respective concentration-time profiles could be described by one-compartment body models with first-order elimination. One additional metabolite compartment with first-order elimination was found appropriate to capture the pharmacokinetics of sutezolid-M1. Once allometrically scaled to humans with a fixed exponent of 0.75 for apparent clearance and 1 for apparent volume of distribution, the AUCs of tedizolid and sutezolid were predicted reasonably well, whereas Cmax was under-predicted for sutezolid. Both NHP and humanized concentration-time profiles will now be used in vitro hollow-fiber pharmacodynamic experiments to determine if differences in drug exposures result in differences in Mycobacterium tuberculosis kill and emergence of resistance.
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