Nontuberculous Mycobacterial Infection in Wisconsin Adults and Its Relationship to Race and Social Disadvantage.

Rationale: Population-based data on the epidemiology of nontuberculosis mycobacterial (NTM) infections are limited, particularly with respect to variation in NTM infection among racial groups and socioeconomic strata. Wisconsin is one of a handful of states where mycobacterial disease is notifiable, allowing large, population-based analyses of the epidemiology of NTM infection in this state. Objectives: To estimate the incidence of NTM infection in Wisconsin adults, describe the geographic distribution of NTM infection across the state, identify the frequency and type of infection caused by different NTM species, and investigate associations between NTM infection and demographics and socioeconomic status. Methods: We conducted a retrospective cohort study using laboratory reports of all NTM isolates from Wisconsin residents submitted to the Wisconsin Electronic Disease Surveillance System from 2011 to 2018. For the analyses of NTM frequency, multiple reports from the same individual were enumerated as separate isolates when nonidentical, collected from different sites or collected more than one year apart. Results: A total of 8,135 NTM isolates from 6,811 adults were analyzed. Mycobacterium avium complex accounted for 76.4% of respiratory isolates. The M. chelonae-abscessus group was the most common species isolated from skin and soft tissue. The annual incidence of NTM infection was stable over the study period (from 22.1 per 100,000 to 22.4 per 100,000). The cumulative incidence of NTM infection among Black (224 per 100,000) and Asian (244 per 100,000) individuals was significantly higher compared with that among their White counterparts (97 per 100,000). Total NTM infections were significantly more frequent (P < 0.001) in individuals from disadvantaged neighborhoods, and racial disparities in the incidence of NTM infection generally remained consistent when stratified by measures of neighborhood disadvantage. Conclusions: More than 90% of NTM infections were from respiratory sites, with the vast majority caused by M. avium complex. Rapidly growing mycobacteria predominated as skin and soft tissue pathogens and were important minor respiratory pathogens. We found a stable annual incidence of NTM infection in Wisconsin between 2011 and 2018. NTM infection occurred more frequently in non-White racial groups and in individuals experiencing social disadvantage, suggesting that NTM disease may be more frequent in these groups as well.

Antimicrobial stewardship in solid organ transplantation: Perspective from a Veterans Affairs Medical Center.

BACKGROUND: The importance of antimicrobial stewardship (AMS) activities specifically focused on solid organ transplant (SOT) recipients is increasingly recognized. In 2014, the Veterans Health Administration (VHA) created national guidance and committed resources to establish AMS programs at Veterans Affairs (VA) medical centers across the country. However, the AMS implementation is at the discretion of individual VA centers. METHODS: We undertook an environmental scan of AMS activities in a tertiary care VA medical center. RESULTS: We describe AMS activities focused on SOT recipients. Strategies based on local epidemiology that leverage the electronic medical record together with engagement by transplant infectious diseases personnel are likely to be beneficial. CONCLUSION: AMS in SOT recipients is challenging yet impactful. Strategies described here may be useful for AMS activities focused on the SOT population.

Mycobacterium bovis BCG osteoarticular infection complicating immune therapy for bladder cancer: a case report.

Osteoarticular infection with Mycobacterium bovis (M. bovis) is a rare complication of bladder cancer treatment with intravesical Bacillus Calmette-Guèrin (BCG). We describe a case of disseminated Mycobacterium bovis BCG infection masquerading as a chronic prosthetic joint infection in a patient with several risk factors for progressive mycobacterial infection.

Powassan Virus Infection Likely Acquired Through Blood Transfusion Presenting as Encephalitis in a Kidney Transplant Recipient.

A kidney transplant patient without known tick exposure developed encephalitis 3 weeks after transplantation. During the transplant hospitalization, the patient had received a blood transfusion from an asymptomatic donor later discovered to have been infected with Powassan virus. Here, we describe a probable instance of transfusion-transmitted Powassan virus infection.

Toll-like receptor chaperone HSP90B1 and the immune response to Mycobacteria.

RATIONALE: HSP90B1, also known as gp96, is a chaperone for multiple Toll-like receptors (TLRs) and is necessary for TLR-mediated inflammatory responses in murine myeloid cells. The molecule is also expressed in T-cells though its specific role is unknown. We hypothesized that human HSP90B1 regulates monocyte and T-cell responses to Mycobacterium tuberculosis (Mtb) and bacilli Calmette-Guerin (BCG) and that its variants are associated with susceptibility to TB disease. METHODS: We screened 17 haplotype-tagging SNPs in the HSP90B1 gene region for association with BCG-induced T-cell cytokine responses using both an ex-vivo whole blood assay (N = 295) and an intracellular cytokine staining assay (N = 180) on samples collected 10 weeks after birth. Using a case-control study design, we evaluated the same SNPs for association with TB disease in a South African pediatric cohort (N = 217 cases, 604 controls). A subset of these SNPs was evaluated for association with HSP90B1 expression in human monocytes, monocyte-derived dendritic cells, and T-cells using RT-PCR. Lastly, we used CRISPR/Cas9 gene editing to knock down HSP90B1 expression in a human monocyte cell line (U937). Knockdown and control cell lines were tested for TLR surface expression and control of Mtb replication. RESULTS: We identified three SNPs, rs10507172, rs10507173 and rs1920413, that were associated with BCG-induced IL-2 secretion (p = 0.017 for rs10507172 and p = 0.03 for rs10507173 and rs1920413, Mann-Whitney, dominant model). SNPs rs10507172 and rs10507173 were associated with TB disease in an unadjusted analysis (p = 0.036 and 0.025, respectively, dominant model) that strengthened with sensitivity analysis of the definite TB cases, which included only those patients with microbiologically confirmed Mtb (p = 0.007 and 0.012, respectively). Knockdowns of HSP90B1 in monocyte cell lines with CRISPR did not alter TLR2 surface expression nor influence Mtb replication relative to controls. CONCLUSION: Among infants, an HSP90B1 gene-region variant is associated with BCG-induced IL-2 production and may be associated with protection from TB disease. HSP90B1 knockdown in human monocyte-like cell lines did not influence TLR2 surface localization nor Mtb replication. Together, these data suggest that HSP90B1 regulates T-cell, but not monocyte, responses to mycobacteria in humans.

Leprosy and the human genome.

Despite the availability of effective treatment for several decades, leprosy remains an important medical problem in many regions of the world. Infection with Mycobacterium leprae can produce paucibacillary disease, characterized by well-formed granulomas and a Th1 T-cell response, or multibacillary disease, characterized by poorly organized cellular infiltrates and Th2 cytokines. These diametric immune responses confer states of relative resistance or susceptibility to leprosy, respectively, and have well-defined clinical manifestations. As a result, leprosy provides a unique opportunity to dissect the genetic basis of human in vivo immunity. A series of studies over the past 40 years suggests that host genes influence the risk of leprosy acquisition and the predilection for different clinical forms of the disease. However, a comprehensive, cellular, and molecular view of the genes and variants involved is still being assembled. In this article, we review several decades of human genetic studies of leprosy, including a number of recent investigations. We emphasize genetic analyses that are validated by the replication of the same phenotype in independent studies or supported by functional experiments demonstrating biological mechanisms of action for specific polymorphisms. Identifying and functionally exploring the genetic and immunological factors that underlie human susceptibility to leprosy have yielded important insights into M. leprae pathogenesis and are likely to advance our understanding of the immune response to other pathogenic mycobacteria. This knowledge may inform new treatment or vaccine strategies for leprosy or tuberculosis.

Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction.

Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-kappaB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29-0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31-0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability.