Vibrio cholerae transitions between aquatic environmental reservoirs and infection in the gastrointestinal tracts of human hosts. The second-messenger molecule cyclic di-GMP (c-di-GMP) and quorum sensing (QS) are important signaling systems that enable V. cholerae to alternate between these distinct environments by controlling biofilm formation and virulence factor expression. Here we identify a conserved regulatory mechanism in V. cholerae that integrates c-di-GMP and QS to control the expression of two transcriptional regulators: aphA, an activator of virulence gene expression and an important regulator of the quorum-sensing pathway, and vpsT, a transcriptional activator that induces biofilm formation. Surprisingly, aphA expression was induced by c-di-GMP. Activation of both aphA and vpsT by c-di-GMP requires the transcriptional activator VpsR, which binds to c-di-GMP. The VpsR binding site at each of these promoters overlaps with the binding site of HapR, the master QS regulator at high cell densities. Our results suggest that V. cholerae combines information conveyed by QS and c-di-GMP to appropriately respond and adapt to divergent environments by modulating the expression of key transcriptional regulators.Bacteria use multiple signaling pathways to monitor and respond appropriately to changing surroundings. Small-molecule chemical signals convey information about the presence, nature, number, and characteristics of the surrounding bacterial species as well as the composition of the environment. Proper responses to changing environments are vital to the survival of bacteria. Vibrio cholerae, the causative agent of cholera, alternates between a motile, virulent state within the host and a sessile, biofilm state in aquatic environmental reservoirs (15). Quorum sensing (QS) and cyclic di-GMP (c-di-GMP) signaling are two chemical signaling systems that control this transition (19).QS allows bacteria to sense the population density and species composition of the surrounding bacterial consortium through the secretion and detection of chemical signals called autoinducers so as to collectively control behaviors (46). In V. cholerae, in the high-cell-density QS state, both biofilm formation and virulence factor expression are repressed (21, 31). c-di-GMP is a nearly ubiquitous bacterial second messenger that induces biofilm formation and represses motility (19). In contrast to QS, c-di-GMP activates the expression of genes necessary for biofilm formation in V. cholerae (3). However, like QS, c-di-GMP is thought to repress the expression of virulence factors (38, 42).The QS regulatory pathways that control biofilm formation and virulence factor expression have been largely elucidated. HapR, the master high-cell-density regulator of the QS signaling cascade, represses biofilm formation by directly binding to the biofilm activator vpsT and inhibiting its transcription (45). Additionally, HapR production reduces intracellular c-di-GMP levels (45). Inhibition of virulence factor expression by QS is mediated by HapR repre...

The potential impact of COVID-19-related disruption on tuberculosis burden To the Editor: Before the coronavirus disease 2019 (COVID-19) pandemic, over 4000 people were dying from tuberculosis (TB) every day [1]. As with past emergencies [2], the impact of COVID-19 on TB outcomes is a serious cause for concern [3] but is currently unknown. Health system overload, due to high numbers of COVID-19 cases, as well as interventions necessary to limit the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could result in severe reductions in health service availability and access for the detection and treatment of TB cases [4]. However, physical distancing interventions could also limit Mycobacterium tuberculosis transmission outside of households, where most transmission occurs [5]. This has not been adequately explored in concurrent work [6-8], and it is currently unclear whether social distancing could compensate for disruptions in TB services, and what the impact of these combined COVID-19 disruption effects on TB burden is likely to be.

Mathematical models are useful for assessing the potential epidemiological impact of future tuberculosis (TB) vaccines. We conducted a systematic review of mathematical models estimating the epidemiological impact of future human TB vaccines. PubMed, Embase and WHO Global Health Library were searched, 3-stage manual sifted, and citation- and reference-tracked, identifying 23 papers. An adapted quality assessment tool was developed, with a resulting median study quality score of 20/28. The literature remains divided as to whether vaccines effective pre- or post-infection would provide greatest epidemiological impact. However, all-age or adolescent/adult targeted prevention of disease vaccines achieve greater and more rapid impact than neonatal vaccines. Mass campaigns alongside routine neonatal vaccination can have profound additional impact. Economic evaluations found TB vaccines overwhelmingly cost-effective, particularly when targeted to adolescents/adults. The variability of impact by setting, age group and vaccine characteristics must be accounted for in the development and delivery of future TB vaccines.

Many national guidelines recommend annual influenza vaccination of immunocompromised patients, although the decision to vaccinate is usually at clinical discretion. We conducted a systematic review and meta-analyses to assess the evidence for influenza vaccination in this group, and we report our results by etiology. Meta-analyses showed significantly lower odds of influenza-like illness after vaccination in patients with human immunodeficiency virus (HIV) infection, patients with cancer, and transplant recipients and of laboratory-confirmed influenza in HIV-positive patients, compared with patients receiving placebo or no vaccination. Pooled odds of seroconversion and seroprotection were typically lower in HIV-positive patients, patients with cancer, and transplant recipients, compared with immunocompetent controls. Vaccination was generally well tolerated, with variation in mild adverse events between etiological groups. Limited evidence of a transient increase in viremia and a decrease in the percentage of CD4(+) cells in HIV-positive patients was found although not accompanied by worsening of clinical symptoms. Clinical judgment remains important when discussing the benefits and safety profile with immunocompromised patients.

More effective tuberculosis vaccines are needed to help reach World Health Organization tuberculosis elimination goals. Insufficient evidence exists on the potential impact of future tuberculosis vaccines with varying characteristics and in different epidemiological settings. To inform vaccine development decision making, we modeled the impact of hypothetical tuberculosis vaccines in three high-burden countries. We calibrated Mycobacterium tuberculosis (M.tb) transmission models to age-stratified demographic and epidemiological data from China, South Africa, and India. We varied vaccine efficacy to prevent infection or disease, effective in persons M.tb uninfected or infected, and duration of protection. We modeled routine early-adolescent vaccination and 10-yearly mass campaigns from 2025. We estimated median percentage population-level tuberculosis incidence rate reduction (IRR) in 2050 compared to a no new vaccine scenario. In all settings, results suggested vaccines preventing disease in M.tb-infected populations would have greatest impact by 2050 (10-year, 70% efficacy against disease, IRR 51%, 52%, and 54% in China, South Africa, and India, respectively). Vaccines preventing reinfection delivered lower potential impact (IRR 1, 12, and 17%). Intermediate impact was predicted for vaccines effective only in uninfected populations, if preventing infection (IRR 21, 37, and 50%) or disease (IRR 19, 36, and 51%), with greater impact in higher-transmission settings. Tuberculosis vaccines have the potential to deliver substantial population-level impact. For prioritizing impact by 2050, vaccine development should focus on preventing disease in M.tb-infected populations. Preventing infection or disease in uninfected populations may be useful in higher transmission settings. As vaccine impact depended on epidemiology, different development strategies may be required.