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Cell-mediated immune responses are known to be critical for control of mycobacterial infections whereas the role of B cells and humoral immunity is unclear. B cells can modulate immune responses by secretion of immunoglobulin, production of cytokines and antigen-presentation. To define the impact of B cells in the absence of secreted immunoglobulin, we analyzed the progression of Mycobacterium tuberculosis (Mtb) infection in mice that have B cells but which lack secretory immunoglobulin (AID(-/-)µS(-/-)mice). AID(-/-)µS(-/-) mice accumulated a population of activated B cells in the lungs when infected and were more susceptible to aerosol Mtb when compared to wild type (C57BL/6) mice or indeed mice that totally lack B cells. The enhanced susceptibility of AID(-/-)µS(-/-) mice was not associated with defective T cell activation or expression of a type 1 immune response. While delivery of normal serum to AID(-/-)µS(-/-) mice did not reverse susceptibility, susceptibility in the spleen was dependent upon the presence of B cells and susceptibility in the lungs of AID(-/-)µS(-/-)mice was associated with elevated expression of the cytokines IL-6, GM-CSF, IL-10 and molecules made by alternatively activated macrophages. Blocking of IL-10 signaling resulted in reversal of susceptibility in the spleens and lungs of AID(-/-)µS(-/-) mice. These data support the hypothesis that B cells can modulate immunity to Mtb in an organ specific manner via the modulation of cytokine production and macrophage activation.

Interferon-γ is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-γ response by CD4 + T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4 + T cell population in the lung. The recall response of the IL-17-producing CD4 + T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4 + T cells producing interferon-γ in the lung. We propose that vaccination induces IL-17-producing CD4 + T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4 + T cells producing interferon-γ, which ultimately restrict bacterial growth.

CD4⁺ T cell responses to aerosol Mycobacterium tuberculosis (Mtb) infection are characterized by the relatively delayed appearance of effector T cells in the lungs. This delay in the adaptive response is likely critical in allowing the bacteria to establish persistent infection. Because of limitations associated with the detection of low frequencies of naïve T cells, it had not been possible to precisely determine when and where naïve antigen-specific T cells are first activated. We have addressed this problem by using early secreted antigenic target 6 (ESAT-6)-specific transgenic CD4 T cells to monitor early T cell activation in vivo. By using an adoptive transfer approach, we directly show that T cell priming to ESAT-6 occurs only after 10 days of infection, is initially restricted to the mediastinal lymph nodes, and does not involve other lymph nodes or the lungs. Primed CD4 T cells rapidly differentiated into proliferating effector cells and ultimately acquired the ability to produce IFN-γ and TNF-α ex vivo. Initiation of T cell priming was enhanced by two full days depending on the magnitude of the challenge inoculum, which suggests that antigen availability is a factor limiting the early CD4 T cell response. These data define a key period in the adaptive immune response to Mtb infection.

Monitoring the concentration of antiretroviral drugs is critical to ensuring patient adherence to HIV treatment and prevention regimens, which is crucial for drug efficacy. These tools may also be useful for screening samples at blood donation centers to avert potential new infections. The current benchmark method to support antiretroviral drug monitoring, liquid chromatography coupled to mass spectrometry (LC‐MS), requires centralized facilities with costly instrumentation, and has blood‐to‐result turnaround times of days to weeks, making it impractical for effective drug monitoring. Seeking to overcome this issue, an aptamer is developed for the antiretroviral drug emtricitabine, which is present in most antiretroviral combination therapies in the market and used for both infection management and prevention. The aptamer has clinically relevant sensitivity in biofluids and is highly selective relative to close analogs such as cytosine, cytidine, fluorocytidine, and lamivudine (a.k.a. 3TC). Using this aptamer, two analytical assays are developed, one for continuous, in‐vivo emtricitabine monitoring in rodent research models, and one for rapid and high‐throughput screening of emtricitabine levels in human plasma. Through blinded analytical validation, this clinical assay achieved an 86.9% positive and 100% negative correlation, with an overall agreement rate of 95% relative to the benchmark LC‐MS method. Monitoring antiretroviral drug levels ensures adherence to HIV treatment and prevention. An emtricitabine‐specific aptamer is developed for in‐vivo monitoring in rodent models and rapid human plasma screening. Validated against LC‐MS, our clinical assay achieved 95% agreement, supporting its utility in managing emtricitabine‐based therapies for infection control and prevention.

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F–producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

Interferon-γ is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-γ response by [CD4.sup.+] T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing [CD4.sup.+] T cell population in the lung. The recall response of the IL-17-producing [CD4.sup.+] T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of [CD4.sup.+] T cells producing interferon-y in the lung. We propose that vaccination induces IL-17-producing [CD4.sup.+] T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit [CD4.sup.+] T cells producing interferon-γ, which ultimately restrict bacterial growth.

Introduction Oral pre‐exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is highly effective in preventing HIV infection among men who have sex with men (MSM). The effects of consistent personal lubricant use in the rectum on tissue PrEP drug concentrations and the rectal microbiota are unknown. We investigated rectal PrEP drug concentrations and the microbiota in MSM before and after repeated rectal application of a hyperosmolar lubricant. Methods We randomized 60 HIV‐negative MSM to apply 4 mL of hyperosmolar rectal lubricant daily (n = 20), take daily oral TDF/FTC (n = 19), or both (n = 21) for seven days. Blood, rectal biopsies and rectal secretions were collected via rigid sigmoidoscopy before and on day 8 after product use. Tenofovir (TFV) and FTC as well as their intracellular metabolites tenofovir‐diphosphate (TFV‐DP), FTC‐triphosphate (FTC‐TP) were measured by HPLC‐mass spectrometry. Rectal mucosal microbiota was sequenced with 16S rRNA sequencing using Illumina MiSeq. Results Seven days of lubricant application was not associated with differences in PrEP drug concentrations in rectal tissue or secretions. Lubricant use was associated with a decrease in the relative abundance of the Bacteroides genus (p = 0.01) and a non‐significant increase in the Prevotella genus (p = 0.09) in the rectum. PrEP drug concentrations in rectal tissue and secretions were not associated with microbiota composition or diversity either before or after lubricant use. Conclusions Repeated rectal application of a hyperosmolar lubricant does not affect mucosal PrEP drug concentrations but is associated with changes in the rectal microbiome.

IntroductionOral pre‐exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is highly effective in preventing HIV infection among men who have sex with men (MSM). The effects of consistent personal lubricant use in the rectum on tissue PrEP drug concentrations and the rectal microbiota are unknown. We investigated rectal PrEP drug concentrations and the microbiota in MSM before and after repeated rectal application of a hyperosmolar lubricant.MethodsWe randomized 60 HIV‐negative MSM to apply 4 mL of hyperosmolar rectal lubricant daily (n = 20), take daily oral TDF/FTC (n = 19), or both (n = 21) for seven days. Blood, rectal biopsies and rectal secretions were collected via rigid sigmoidoscopy before and on day 8 after product use. Tenofovir (TFV) and FTC as well as their intracellular metabolites tenofovir‐diphosphate (TFV‐DP), FTC‐triphosphate (FTC‐TP) were measured by HPLC‐mass spectrometry. Rectal mucosal microbiota was sequenced with 16S rRNA sequencing using Illumina MiSeq.ResultsSeven days of lubricant application was not associated with differences in PrEP drug concentrations in rectal tissue or secretions. Lubricant use was associated with a decrease in the relative abundance of the Bacteroides genus (p = 0.01) and a non‐significant increase in the Prevotella genus (p = 0.09) in the rectum. PrEP drug concentrations in rectal tissue and secretions were not associated with microbiota composition or diversity either before or after lubricant use.ConclusionsRepeated rectal application of a hyperosmolar lubricant does not affect mucosal PrEP drug concentrations but is associated with changes in the rectal microbiome.

Cell-mediated immune responses are known to be critical for control of mycobacterial infections whereas the role of B cells and humoral immunity is unclear. B cells can modulate immune responses by secretion of immunoglobulin, production of cytokines and antigen-presentation. To define the impact of B cells in the absence of secreted immunoglobulin, we analyzed the progression of Mycobacterium tuberculosis (Mtb) infection in mice that have B cells but which lack secretory immunoglobulin (AID-/- mu S-/-mice). AID-/- mu S-/- mice accumulated a population of activated B cells in the lungs when infected and were more susceptible to aerosol Mtb when compared to wild type (C57BL/6) mice or indeed mice that totally lack B cells. The enhanced susceptibility of AID-/- mu S-/- mice was not associated with defective T cell activation or expression of a type 1 immune response. While delivery of normal serum to AID-/- mu S-/- mice did not reverse susceptibility, susceptibility in the spleen was dependent upon the presence of B cells and susceptibility in the lungs of AID-/- mu S-/-mice was associated with elevated expression of the cytokines IL-6, GM-CSF, IL-10 and molecules made by alternatively activated macrophages. Blocking of IL-10 signaling resulted in reversal of susceptibility in the spleens and lungs of AID-/- mu S-/- mice. These data support the hypothesis that B cells can modulate immunity to Mtb in an organ specific manner via the modulation of cytokine production and macrophage activation.

Interferon-[gamma] is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon- [gamma] response by CD4 super(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4 super(+) T cell population in the lung. The recall response of the IL-17-producing CD4 super(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4 super(+) T cells producing interferon-[gamma] in the lung. We propose that vaccination induces IL-17-producing CD4 super(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4 super(+) T cells producing interferon-[gamma], which ultimately restrict bacterial growth.