Immunological Augmentation may yield Improved Treatment of Severe Covid-19 Infection

Science

SARS-CoV-2 highlighted to many in the research community that our understanding of inflammatory and fibrotic processes is still unclear, and despite significant progress in the field of immunotherapy and biologics in augmenting these processes, as seen with the dawn of monoclonal antibodies and RNA vaccines, we still have a great deal to learn.

Recent research aimed to elucidate these complex processes in the lungs of patients with severe Covid-19 infection, with the hope of identifying promising therapeutic targets for future intervention. One team at The Ohio State University College of Medicine, Columbus, looked into the role of the enzyme caspase-4/11 in the inflammatory process associated with severe Covid-19 infection and have found evidence that the enzyme is involved in dysregulated inflammation, tissue injury, and the formation of blood clots in the lungs.

“Immunological Augmentation may yield Improved Treatment of Severe Covid-19 Infection“

Research into caspase-4 was carried out on mouse model, using the murine homolog of the enzyme, caspase-11, looking into the role of the enzyme in the formation of the non-canonical inflammasome which underlies the uncontrollable inflammatory and prothrombotic pathological processes associated with severe SARS-CoV-2 infection. Researchers found that mice with SARS-CoV-2 infection demonstrated an upregulation of caspase-11 compared to health controls, which is in line with the finding that caspase-4 is upregulated in humans with SARS-CoV-2 infection. Furthermore, the severity of disease correlated with the level of caspase-4 expression in human patients. Finally, mice engineered to be deficient in caspase-11 showed reduced lung pathology and reduced weight loss compared to their wild-type counterparts. Although viral titres were similar between control and experimental groups, expression of inflammatory molecules, including interleukin (IL)-1β, IL-6, and CXCL1, neutrophil activity, and von Willebrand factor were reduced in the lungs of caspase-11 knockout mice. These differences indicate a more restrained inflammatory response against the virus, and a lesser degree of vascular endothelial damage, respectively. In addition, there was greater expression of the transcription factor Kruppel-like Factor 2, an indicator of vascular integrity, in caspase-11 knockout mice. This suggests that caspase-4 in humans is involved in the cytokine storm associated with hyperinflammatory states and multi-organ failure in severe covid-19 cases.

The same lab has begun testing an enzymatic blocking agent that works to hinder caspase-11 activity with the goal of creating a new treatment for use in severe covid, and other health conditions similarly characterised by hyperinflammatory cascades and thrombotic sequelae, offering a more nuanced approach to augmenting the inflammatory response. By limiting this process through augmenting the activity of this enzyme, scientists hope to provide a treatment that will reduce respiratory damage, improve patient outcomes, and increase survival. Given the massive demand placed on intensive care during the pandemic, any treatments that limit disease progression to a point where intensive intervention is required also limits the demand on services, and reduces the risks patients face on being stepped-up to intensive care. These include ventilator-associated pneumonia, catheter-associated urinary tract infections, sepsis, venous thromboembolism, critical illness polyneuropathy and myopathy, disuse atrophy due to immobility, and long-term neuropsychiatric changes, including post-traumatic stress disorder, depression, anxiety, (https://journals.lww.com/ccmjournal/fulltext/2011/02000/Long_term_complications_of_critical_care.19.aspx?casa_token=JXSuUtXcWv8AAAAA:kCvAlF-pRvxtVe9LQLfUfq_e6ZavB513CELV7KNYOG3ws0OcBvPIT1h5iBPhhMyLERfOW41p3THv_tWV-Q24Ibid2HoOgg)( https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/hospital-medicine/complications-of-intensive-care-unit-care/). Respiratory compromise resulting from inflammatory damage within the lungs was a major indicators for a confirmed SARS-CoV-2 patient to be admitted onto the intensive care unit, and by offsetting this disease progression, the risk of complications in these patients will be reduced, hopefully improving recovery time and long-term health outcomes.

https://www.worldpharmanews.com/research/6059-blocking-enzyme-could-hold-the-key-to-preventing-treating-severe-covid-19

https://www.pnas.org/doi/full/10.1073/pnas.2202012119

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