Methamphetamine (METH) is a major addictive drug of abuse in the United States and worldwide, and its use is linked to HIV acquisition. The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis in patients with AIDS. In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity. Using a systemic mouse model of infection and in vitro assays in order to critically assess the impact of METH on C. neoformans pathogenesis, we demonstrate that METH stimulates fungal adhesion, glucuronoxylomannan (GXM) release, and biofilm formation in the lungs. Interestingly, structural analysis of the capsular polysaccharide of METH-exposed cryptococci revealed that METH alters the carbohydrate composition of this virulence factor, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Additionally, we show that METH promotes C. neoformans dissemination from the respiratory tract into the brain parenchyma. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms.
SARS-CoV-2 has initiated a global pandemic and several vaccines have now received emergency use authorization. Using the reference strain SARS-CoV-2 USA-WA1/2020, we evaluated modes of transmission and the ability of prior infection or vaccine-induced immunity to protect against infection in ferrets. Ferrets were semi-permissive to infection with the USA-WA1/2020 isolate. When transmission was assessed via the detection of vRNA at multiple timepoints, direct contact transmission was efficient to 3/3 and 3/4 contact animals in two respective studies, while respiratory droplet transmission was poor to only 1/4 contact animals. To determine if previously infected ferrets were protected against re-infection, ferrets were re-challenged 28 or 56 days post-infection. Following viral challenge, no infectious virus was recovered in nasal wash samples. In addition, levels of vRNA in the nasal wash were several orders of magnitude lower than during primary infection, and vRNA was rapidly cleared. To determine if intramuscular vaccination protected ferrets, ferrets were vaccinated using a prime-boost strategy with the S-protein receptor-binding domain formulated with an oil-in-water adjuvant. Upon viral challenge, none of the mock or vaccinated animals were protected against infection, and there were no significant differences in vRNA or infectious virus titers in the nasal wash. Combined these studies demonstrate that in ferrets direct contact is the predominant mode of transmission of the USA-WA1/2020 isolate and immunity to SARS-CoV-2 is maintained for at least 56 days. Our studies also indicate protection of the upper respiratory tract against SARS-CoV-2 will require vaccine strategies that mimic natural infection or induce site-specific immunity. Importance: The SARS-CoV-2 USA-WA1/2020 strain is a CDC reference strain used by multiple research laboratories. Here, we show the predominant mode of transmission of this isolate in ferrets is by direct contact. We further demonstrate ferrets are protected against re-infection for at least 56 days even when levels of neutralizing antibodies are low or undetectable. Last, we show that when ferrets were vaccinated by the intramuscular route to induce antibodies against SARS-CoV-2, ferrets remain susceptible to infection of the upper respiratory tract. Collectively, these studies suggest protection of the upper respiratory tract will require vaccine approaches that mimic natural infection.
In response to the current urgent demand for N95 respirators by healthcare workers responding to the COVID-19 pandemic, with particular emphasis on needs within local medical systems, we initiated an N95 decontamination study using aerosolized hydrogen peroxide or aHP (7% H2O2 solution), via the Pathogo Curis® (Curis) decontamination system. The study has thus far included 10 cycles of respirator decontamination, with periodic qualitative and quantitative fit testing to verify ongoing respirator integrity through the decontamination process, and support a statistical evaluation of successful respirator fit. In addition, we have conducted virologic testing of respirator surfaces and materials to demonstrate a rigorous verification of decontamination.Given that the current pandemic entails a respiratory viral pathogen, it is critical to address these aspects of respirator safety for reuse. These measures are intended to provide a foundation for a suitable decontamination process, which maintains N95 function, and supports safe respirator reuse by healthcare providers. Current results from both respirator fit testing and virologic testing indicate that the process is effective on the basis of zero failure rate on fit-testing of selected respirators, and on complete decontamination of multiple virus species by aHP treatment, comparable to that observed with commercial spore-based biological indicators of sterilization.
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