Serological Evidence of Mpox Virus Infection During Peak Mpox Transmission in New York City, July to August 2022.

BACKGROUND: The extent to which infections may have been undetected in an epicenter of the 2022 mpox outbreak is unknown. METHODS: A serosurvey (July and August 2022) assessed the seroprevalence and correlates of mpox infection among a diverse sample of asymptomatic patients with no prior mpox diagnoses and no known histories of smallpox or mpox vaccination. We present seropositivity stratified by participant characteristics collected via survey. RESULTS: Two-thirds of 419 participants were cismen (281 of 419), of whom 59.1% (166 of 281) reported sex with men (MSM). The sample also included 109 ciswomen and 28 transgender/gender nonconforming/nonbinary individuals. Overall seroprevalence was 6.4% (95% confidence interval [CI], 4.1%-8.8%); 3.7% among ciswomen (95% CI, 1.0%-9.1%), 7.0% among cismen with only ciswomen partners (95% CI, 2.0%-11.9%), and 7.8% among MSM (95% CI, 3.7%-11.9%). There was little variation in seroprevalence by race/ethnicity, age group, HIV status, or number of recent sex partners. No participants who reported close contact with mpox cases were seropositive. Among participants without recent mpox-like symptoms, 6.3% were seropositive (95% CI, 3.6%-9.0%). CONCLUSIONS: Approximately 1 in 15 vaccine-naive people in our study had antibodies to mpox during the height of the NYC outbreak, indicating the presence of asymptomatic infections that could contribute to ongoing transmission.

Epidemiologic and Clinical Characteristics of Monkeypox Cases - United States, May 17-July 22, 2022.

Monkeypox, a zoonotic infection caused by an orthopoxvirus, is endemic in parts of Africa. On August 4, 2022, the U.S. Department of Health and Human Services declared the U.S. monkeypox outbreak, which began on May 17, to be a public health emergency (1,2). After detection of the first U.S. monkeypox case), CDC and health departments implemented enhanced monkeypox case detection and reporting. Among 2,891 cases reported in the United States through July 22 by 43 states, Puerto Rico, and the District of Columbia (DC), CDC received case report forms for 1,195 (41%) cases by July 27. Among these, 99% of cases were among men; among men with available information, 94% reported male-to-male sexual or close intimate contact during the 3 weeks before symptom onset. Among the 88% of cases with available data, 41% were among non-Hispanic White (White) persons, 28% among Hispanic or Latino (Hispanic) persons, and 26% among non-Hispanic Black or African American (Black) persons. Forty-two percent of persons with monkeypox with available data did not report the typical prodrome as their first symptom, and 46% reported one or more genital lesions during their illness; 41% had HIV infection. Data suggest that widespread community transmission of monkeypox has disproportionately affected gay, bisexual, and other men who have sex with men and racial and ethnic minority groups. Compared with historical reports of monkeypox in areas with endemic disease, currently reported outbreak-associated cases are less likely to have a prodrome and more likely to have genital involvement. CDC and other federal, state, and local agencies have implemented response efforts to expand testing, treatment, and vaccination. Public health efforts should prioritize gay, bisexual, and other men who have sex with men, who are currently disproportionately affected, for prevention and testing, while addressing equity, minimizing stigma, and maintaining vigilance for transmission in other populations. Clinicians should test patients with rash consistent with monkeypox,† regardless of whether the rash is disseminated or was preceded by prodrome. Likewise, although most cases to date have occurred among gay, bisexual, and other men who have sex with men, any patient with rash consistent with monkeypox should be considered for testing. CDC is continually evaluating new evidence and tailoring response strategies as information on changing case demographics, clinical characteristics, transmission, and vaccine effectiveness become available.§.

Contributions of TolC Orthologs to Francisella tularensis Schu S4 Multidrug Resistance, Modulation of Host Cell Responses, and Virulence.

Francisella tularensis is a Gram-negative, facultative intracellular pathogen and the causative agent of tularemia. Previous studies with the attenuated live vaccine strain (LVS) identified a role for the outer membrane protein TolC in modulation of host cell responses during infection and virulence in the mouse model of tularemia. TolC is an integral part of efflux pumps that export small molecules and type I secretion systems that export a range of bacterial virulence factors. In this study, we analyzed TolC and its two orthologs, FtlC and SilC, present in the fully virulent F. tularensis Schu S4 strain for their contributions to multidrug efflux, suppression of innate immune responses, and virulence. We found that each TolC ortholog participated in multidrug efflux, with overlapping substrate specificities for TolC and FtlC and a distinct substrate profile for SilC. In contrast to their shared roles in drug efflux, only TolC functioned in the modulation of macrophage apoptotic and proinflammatory responses to Schu S4 infection, consistent with a role in virulence factor delivery to host cells. In agreement with previous results with the LVS, the Schu S4 ΔtolC mutant was highly attenuated for virulence in mice by both the intranasal and intradermal routes of infection. Unexpectedly, FtlC was also critical for Schu S4 virulence, but only by the intradermal route. Our data demonstrate a conserved and critical role for TolC in modulation of host immune responses and Francisella virulence and also highlight strain- and route-dependent differences in the pathogenesis of tularemia.

Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases.

The Suppressor of TCR signaling proteins (Sts-1 and Sts-2) are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic lineages, including T lymphocytes. Mice lacking Sts expression are characterized by enhanced T cell responses. Additionally, a recent study demonstrated that Sts-/- mice are profoundly resistant to systemic infection by Candida albicans, with resistance characterized by enhanced survival, more rapid fungal clearance in key peripheral organs, and an altered inflammatory response. To investigate the role of Sts in the primary host response to infection by a bacterial pathogen, we evaluated the response of Sts-/- mice to infection by a Gram-negative bacterial pathogen. Francisella tularensis is a facultative bacterial pathogen that replicates intracellularly within a variety of cell types and is the causative agent of tularemia. Francisella infections are characterized by a delayed immune response, followed by an intense inflammatory reaction that causes widespread tissue damage and septic shock. Herein, we demonstrate that mice lacking Sts expression are significantly resistant to infection by the live vaccine strain (LVS) of F. tularensis Resistance is characterized by reduced lethality following high-dose intradermal infection, an altered cytokine response in the spleen, and enhanced bacterial clearance in multiple peripheral organs. Sts-/- bone marrow-derived monocytes and neutrophils, infected with F. tularensis LVS ex vivo, display enhanced restriction of intracellular bacteria. These observations suggest the Sts proteins play an important regulatory role in the host response to bacterial infection, and they underscore a role for Sts in regulating functionally relevant immune response pathways.

Severe Mpox Among People With Advanced Human Immunodeficiency Virus Receiving Prolonged Tecovirimat in New York City.

Severe mpox has been observed in people with advanced human immunodeficiency virus (HIV). We describe clinical outcomes of 13 patients with advanced HIV (CD4 <200 cells/µL), severe mpox, and multiorgan involvement. Despite extended tecovirimat courses and additional agents, including vaccinia immune globulin, cidofovir, and brincidofovir, this group experienced prolonged hospitalizations and high mortality.

Francisella tularensis disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host.

Francisella tularensis is a zoonotic pathogen and the causative agent of tularemia. F. tularensis replicates to high levels within the cytosol of macrophages and other host cells while subverting the host response to infection. Critical to the success of F. tularensis is its ability to delay macrophage apoptosis to maintain its intracellular replicative niche. However, the host-signaling pathway(s) modulated by F. tularensis to delay apoptosis are poorly characterized. The outer membrane channel protein TolC is required for F. tularensis virulence and its ability to suppress apoptosis and cytokine expression during infection of macrophages. We took advantage of the F. tularensis ∆tolC mutant phenotype to identify host pathways that are important for activating macrophage apoptosis and that are disrupted by the bacteria. Comparison of macrophages infected with wild-type or ∆tolC F. tularensis revealed that the bacteria interfere with TLR2-MYD88-p38 signaling at early times post infection to delay apoptosis, dampen innate host responses, and preserve the intracellular replicative niche. Experiments using the mouse pneumonic tularemia model confirmed the in vivo relevance of these findings, revealing contributions of TLR2 and MYD88 signaling to the protective host response to F. tularensis, which is modulated by the bacteria to promote virulence. IMPORTANCE Francisella tularensis is a Gram-negative intracellular bacterial pathogen and the causative agent of the zoonotic disease tularemia. F. tularensis, like other intracellular pathogens, modulates host-programmed cell death pathways to ensure its replication and survival. We previously identified the outer membrane channel protein TolC as required for the ability of F. tularensis to delay host cell death. However, the mechanism by which F. tularensis delays cell death pathways during intracellular replication is unclear despite being critical to pathogenesis. In the present study, we address this gap in knowledge by taking advantage of ∆tolC mutants of F. tularensis to uncover signaling pathways governing host apoptotic responses to F. tularensis and which are modulated by the bacteria during infection to promote virulence. These findings reveal mechanisms by which intracellular pathogens subvert host responses and enhance our understanding of the pathogenesis of tularemia.