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Fewer than 30 cases of Mycobacterium senegalense infection have been reported. We report a complicated case of M. senegalense infection in Memphis, Tennessee, in the southeastern United States. The patient's comorbidities of past organ transplant and insulin-dependent diabetes required delicate consideration of those health conditions to guide treatment.

The cell surface serine protease Transmembrane Protease 2 (TMPRSS2) is required to cleave the spike protein of SARS-CoV-2 for viral entry into cells. We determined whether negatively-charged heparin enhanced TMPRSS2 inhibition by alpha-1-antitrypsin (AAT). TMPRSS2 activity was determined in HEK293T cells overexpressing TMPRSS2. We quantified infection of primary human airway epithelial cells (hAEc) with human coronavirus 229E (HCoV-229E) by immunostaining for the nucleocapsid protein and by the plaque assay. Detailed molecular modeling was undertaken with the heparin–TMPRSS2–AAT ternary complex. Enoxaparin enhanced AAT inhibition of both TMPRSS2 activity and infection of hAEc with HCoV-229E. Underlying these findings, detailed molecular modeling revealed that: (i) the reactive center loop of AAT adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to an exogenous (nafamostat) or endogenous (HAI-2) TMPRSS2 inhibitor and (ii) negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2–AAT interface, neutralizing otherwise repulsive forces. In conclusion, enoxaparin enhances AAT inhibition of both TMPRSS2 and coronavirus infection. Such host-directed therapy is less likely to be affected by SARS-CoV-2 mutations. Furthermore, given the known anti-inflammatory activities of both AAT and heparin, this form of treatment may target both the virus and the excessive inflammatory consequences of severe COVID-19.

Mycobacterium nebraskense infection is rarely encountered; only 7 human cases have been reported worldwide since the initial report of 5 cases in Nebraska, USA, in 2004. We report 9 patients from Connecticut and 2 from Oregon, USA, who had M. nebraskense isolated from respiratory secretions; 7 patients met the American Thoracic Society/Infectious Diseases Society of America criteria for nontuberculous mycobacterial pulmonary disease. In 4 cases, the organism was isolated 1 time and caused brief or no symptoms. Most cases in Connecticut were reported after 2017. Antimicrobial drug susceptibility testing of 6 isolates showed clarithromycin susceptibility. In 2 cases, infection was refractory to treatment. The 9 Connecticut patients lived in 8 different towns; thus, a common water supply did not explain the high frequency of M. nebraskense isolation. M. nebraskense is a clinically significant cause of nontuberculous mycobacterial pulmonary disease in Connecticut; continued surveillance will be needed to determine its frequency and optimum treatment.

Although coagulation factors play a role in host defense for \"living fossils\" such as horseshoe crabs, the role of the coagulation system in immunity in higher organisms remains unclear. We modeled the interface of human species C adenovirus (HAdv) interaction with coagulation factor X (FX) and introduced a mutation that abrogated formation of the HAdv-FX complex. In vivo genome-wide transcriptional profiling revealed that FX-binding-ablated virus failed to activate a distinct network of nuclear factor kB-dependent early-response genes that are activated by HAdv-FX complex downstream of TLR4/MyD88/TRIF/TRAF6 signaling. Our study implicates host factor \"decoration\" of the virus as a mechanism to trigger an innate immune sensor that responds to a misplacement of coagulation FX from the blood into intracellular macrophage compartments upon virus entry into the cell.

As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to escape Kupffer cell uptake as evidenced by producing no Kupffer cell death in vivo, not requiring predosing in vivo, and being phagocytosed less efficiently by macrophages in vitro compared to Ad5. When tested as a helper-dependent adenovirus (Ad) vector, Ad5/6 mediated higher luciferase and factor IX transgene expression than either helper-dependent adenoviral 5 (HD-Ad5) or HD-Ad6 vectors. These data suggest that the Ad5/6 hexon-chimera evades Kupffer cells and may have utility for systemic and liver-directed therapies.

Polyethylene glycol (PEG) is a hydrophilic polymer that has been used to coat adenoviral (Ad) vectors to improve their pharmacology. To analyze the effects of PEG on Ad5 tropism, Ad5 was covalently modified with different sizes of PEG and in vitro and in vivo transduction was analyzed. All tested PEGs ablated in vitro transduction. When protein C (PC) and factors VII, IX, and X were added, only factors IX and X increased transduction by the PEGylated vectors with the largest effect by X. Inactivation of these factors with warfarin drastically reduced liver transduction in mice by the PEGylated vectors after intravenous (IV) injection. Ad5 conjugated with 5 kd PEG maintained normal liver transduction while conjugation with larger 20 and 35 kd PEGs significantly reduced liver transduction. When intraperitoneal (IP) injection was tested, Ad transduced the peritoneum efficiently with only low level liver transduction. When Ad5 was modified with 5 kd PEG, peritoneal transduction was reduced and the virus preferentially transduced the liver. These data demonstrate the effects of different sizes of PEG on in vivo Ad tropism and suggest that this approach may be useful in retargeting and detargeting Ad in vivo.

Background Staphylococcus aureus (SA) is a leading cause of hospital-acquired infection, including bloodstream infection (BSI), in NICUs. In this study, we evaluated the effect of screening and decolonization of MSSA-colonized babies with mupirocin on the rate of MSSA infection. Patients and Methods. Study design: Sequential time series. Pre-intervention period, January 2015–March 2017; wash out period, April 2017; intervention period, May 2017–March 2018. Population: Neonates admitted to a Level IV NICU with anticipated stay of greater than 2 days. Intervention: A single swab of the nares, umbilicus & groin was sent weekly for SA surveillance culture. MSSA-colonized neonates were decolonized with mupirocin application to nares, umbilicus and abraded skin twice daily for 5 days. Outcome measures: Comparison of rates of MSSA infections during pre- and post-intervention periods. Infections included BSI and skin/wound infections, excluding patients with MSSA from only eye or respiratory specimens. Comparators: Change in rates of Gram-negative and MRSA BSI. Change in rates of MSSA BSI in an affiliated NICU with the same medical staff but no intervention. Results MSSA BSI decreased from 0.37 per 1,000 hospital days (n = 15) to 0.00 (n = 0), P = 0.0092. All MSSA infections decreased from 0.62 (n = 25) to 0.11 (n = 2), P = 0.0078. Of 694 eligible neonates, 98.8% were screened at least once for MSSA colonization, which was detected in 92 (13.4%) infants. Median weekly prevalence of colonization was 6.7%. Median length of stay of neonates after initial detection of colonization was 30 days. Of colonized neonates, 92% received mupirocin treatment, with a median of 1 course of mupirocin treatment per patient (range, 1–7 courses). Of 54 isolates tested, all were mupirocin-susceptible. In contrast, there was no significant change in the rates of either MRSA (P = 0.71) or Gram-negative (P = 0.45) BSIs. In the comparison NICU, there was no significant change in rate of MSSA BSIs (P = 0.34). Conclusion Despite a substantial burden of MSSA-colonized neonates, the intervention was associated with elimination of MSSA BSI and an 82% reduction in rate of MSSA infections. A potential confounding factor was the occurrence of a cluster of mupirocin-resistant MRSA during the intervention period with the associated intensified infection prevention measures. Disclosures All authors: No reported disclosures.