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Tuberculosis is a heterogeneous disease in humans with individuals exhibiting a wide range of susceptibility. This heterogeneity is not captured by standard laboratory mouse lines. We used a new collection of 19 wild-derived inbred mouse lines collected from diverse geographic sites to identify novel phenotypes during Mycobacterium tuberculosis ( Mtb ) infection. Wild-derived mice have heterogeneous immune responses to infection that result in differential ability to control disease at early time points. Correlation analysis with multiple parameters including sex, weight, and cellular immune responses in the lungs revealed that enhanced control of infection is associated with increased numbers of CD4 T cells, CD8 T cells, and B cells. Surprisingly, we did not observe strong correlations between IFN-γ production and control of infection. Although in most lines high neutrophils were associated with susceptibility, we identified a mouse line that harbors high neutrophil numbers yet controls infection. Using single-cell RNA sequencing, we identified a novel neutrophil signature associated with failure to control infection.

Tuberculosis is a heterogeneous disease in humans with individuals exhibiting a wide range of susceptibility. This heterogeneity is not captured by standard laboratory mouse lines. We used a new collection of 19 wild-derived inbred mouse lines collected from diverse geographic sites to identify novel phenotypes during Mycobacterium tuberculosis ( Mtb ) infection. Wild-derived mice have heterogeneous immune responses to infection that result in differential ability to control disease at early time points. Correlation analysis with multiple parameters including sex, weight, and cellular immune responses in the lungs revealed that enhanced control of infection is associated with increased numbers of CD4 T cells, CD8 T cells, and B cells. Surprisingly, we did not observe strong correlations between IFN-γ production and control of infection. Although in most lines high neutrophils were associated with susceptibility, we identified a mouse line that harbors high neutrophil numbers yet controls infection. Using single-cell RNA sequencing, we identified a novel neutrophil signature associated with failure to control infection.

The use of face masks or respirators (N95/KN95) is recommended to reduce transmission of SARS-CoV-2, the virus that causes COVID-19 (1). Well-fitting face masks and respirators effectively filter virus-sized particles in laboratory conditions (2,3), though few studies have assessed their real-world effectiveness in preventing acquisition of SARS-CoV-2 infection (4). A test-negative design case-control study enrolled randomly selected California residents who had received a test result for SARS-CoV-2 during February 18-December 1, 2021. Face mask or respirator use was assessed among 652 case-participants (residents who had received positive test results for SARS-CoV-2) and 1,176 matched control-participants (residents who had received negative test results for SARS-CoV-2) who self-reported being in indoor public settings during the 2 weeks preceding testing and who reported no known contact with anyone with confirmed or suspected SARS-CoV-2 infection during this time. Always using a face mask or respirator in indoor public settings was associated with lower adjusted odds of a positive test result compared with never wearing a face mask or respirator in these settings (adjusted odds ratio [aOR] = 0.44; 95% CI = 0.24-0.82). Among 534 participants who specified the type of face covering they typically used, wearing N95/KN95 respirators (aOR = 0.17; 95% CI = 0.05-0.64) or surgical masks (aOR = 0.34; 95% CI = 0.13-0.90) was associated with significantly lower adjusted odds of a positive test result compared with not wearing any face mask or respirator. These findings reinforce that in addition to being up to date with recommended COVID-19 vaccinations, consistently wearing a face mask or respirator in indoor public settings reduces the risk of acquiring SARS-CoV-2 infection. Using a respirator offers the highest level of personal protection against acquiring infection, although it is most important to wear a mask or respirator that is comfortable and can be used consistently.

To describe the implementation of a test-negative design case-control study in California during the Coronavirus Disease 2019 (COVID-19) pandemic. Test-negative case-control study. Between February 24, 2021 - February 24, 2022, a team of 34 interviewers called 38,470 Californians, enrolling 1,885 that tested positive for SARS-CoV-2 (cases) and 1,871 testing negative for SARS-CoV-2 (controls) for 20-minute telephone survey. We estimated adjusted odds ratios for answering the phone and consenting to participate using mixed effects logistic regression. We used a web-based anonymous survey to compile interviewer experiences. Cases had 1.29-fold (95% CI: 1.24-1.35) higher adjusted odds of answering the phone and 1.69-fold (1.56-1.83) higher adjusted odds of consenting to participate compared to controls. Calls placed from 4pm to 6pm had the highest adjusted odds of being answered. Some interviewers experienced mental wellness challenges interacting with participants with physical (e.g., food, shelter, etc.) and emotional (e.g., grief counseling) needs, and enduring verbal harassment from individuals called. Calls placed during afternoon hours may optimize response rate when enrolling controls to a case-control study during a public health emergency response. Proactive check-ins and continual collection of interviewer experience(s) and may help maintain mental wellbeing of investigation workforce. Remaining adaptive to the dynamic needs of the investigation team is critical to a successful study, especially in emergent public health crises, like that represented by the COVID-19 pandemic.

(Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-γ-producing CD4+ T cells are necessary but insufficient for protection against infection. In humans, the development of IL-17A producing Th17 T cells correlates with protection, however not all individuals develop a Th17 response. In mice, experimental vaccines can elicit protective Th17 cells, yet Th17s are rare in primary infection. Why Mtb fails to consistently elicit Th17s is unknown. Here, we identify factors suppressing Th17 responses during primary infection. We demonstrate that the lack of Th17 induction is independent of route and duration. Next, using deficient mice, we show that Mtb drives a Th1 response that is only partially protective and limits Th17 cell production in an IFN-γ independent manner. We further reveal that the ESX-1 type VII alternative secretion system and lipid PDIM suppresses Th17 responses. Infection with ESX-1 or PDIM mutants results in significantly increased Th17 T cells and IL-17A cytokine in the lungs, and infection of IL-17A deficient animals partially restores virulence of ESX-1 and PDIM mutants. Although the ESX-1 secretion system and lipid PDIM elicits type I IFN, which can suppress Th17 differentiation, we find that suppression of Th17 is independent of type I IFN. Instead, ESX-1 and PDIM suppresses production of IL-23, a cytokine that promotes Th17 differentiation, in dendritic cells found in mediastinal lymph nodes during Mtb infection. These findings define a new function of the ESX-1 secretion system and PDIM in Mtb virulence, a long-standing question in tuberculosis research.

Mycobacterium tuberculosis (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-γ-producing CD4+ T cells are necessary but insufficient for immune protection. Data from humans shows that the development of IL-17a producing Th17 T cells correlates with protection against infection, however not all individuals develop a Th17 response. In mouse models, experimental vaccines can elicit protective Th17 cells, but Th17s are rare in primary infection. Here, we identify factors suppressing Th17 responses during primary Mtb infection. First, using Tbet deficient mice, we demonstrate that Mtb drives a Th1 response that is only partially protective and limits the production of protective Th17 cells in an IFN-γ independent manner. Next, we reveal that the ESX-1 type VII alternative secretion system in Mtb suppresses Th17 responses by inhibiting IL-23 production in dendritic cells. These findings define a new function of the ESX-1 secretion system in Mtb virulence, a long-standing question in tuberculosis research.Mycobacterium tuberculosis (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-γ-producing CD4+ T cells are necessary but insufficient for immune protection. Data from humans shows that the development of IL-17a producing Th17 T cells correlates with protection against infection, however not all individuals develop a Th17 response. In mouse models, experimental vaccines can elicit protective Th17 cells, but Th17s are rare in primary infection. Here, we identify factors suppressing Th17 responses during primary Mtb infection. First, using Tbet deficient mice, we demonstrate that Mtb drives a Th1 response that is only partially protective and limits the production of protective Th17 cells in an IFN-γ independent manner. Next, we reveal that the ESX-1 type VII alternative secretion system in Mtb suppresses Th17 responses by inhibiting IL-23 production in dendritic cells. These findings define a new function of the ESX-1 secretion system in Mtb virulence, a long-standing question in tuberculosis research.

Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for control of bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side-product of glycolysis. Here we show that despite the toxicity of this aldehyde, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system. We use targeted mutations in mice to modulate methylglyoxal generation and show that reducing methylglyoxal production by the host promotes survival of and , whereas increasing methylglyoxal levels improves control of bacterial infection. Furthermore, we show that bacteria that are unable to detoxify methylglyoxal are avirulent and experience up to 1000-fold greater genomic mutation frequency during infection. Taken together, these results suggest that methylglyoxal is an antimicrobial innate immune effector that defends the host against bacterial pathogens.

Tuberculosis (TB) is a heterogenous disease in humans with individuals exhibiting a wide range of susceptibility. This heterogeneity is not captured by standard laboratory mouse lines. We used a new collection of 19 wild-derived inbred mouse lines collected from diverse geographic sites to identify novel phenotypes during ( ) infection. Wild derived mice have heterogenous immune responses to infection that result in differential ability to control disease at early timepoints. Correlation analysis with multiple parameters including sex, weight, and cellular immune responses in the lungs revealed that enhanced control of infection is associated with increased numbers of CD4 T cells, CD8 T cells and B cells. Surprisingly, we did not observe strong correlations between IFN-γ production and control of infection. Although in most lines high neutrophils were associated with susceptibility, we identified a mouse line that harbors high neutrophils numbers yet controls infection. Using single-cell RNA sequencing, we identified a novel neutrophil signature associated with failure to control infection.