Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients: lessons from basic research (inclusive bats), light on conceivable therapies

Abstract

The major risk factors to fatal outcome in COVID-19 patients, i.e., elderliness and pre-existing metabolic and cardiovascular diseases (CVD), share in common the characteristic of being chronic degenerative diseases of inflammatory nature associated with defective heat shock response (HSR). The molecular components of the HSR, the principal metabolic pathway leading to the physiological resolution of inflammation, is an anti-inflammatory biochemical pathway that involves molecular chaperones of the heat shock protein (HSP) family during homeostasis-threatening stressful situations (e.g., thermal, oxidative and metabolic stresses). The entry of SARS coronaviruses in target cells, on the other hand, aggravates the already-jeopardized HSR of this specific group of patients. In addition, cellular counterattack against virus involves interferon (IFN)-mediated inflammatory responses. Therefore, individuals with impaired HSR cannot resolve virus-induced inflammatory burst physiologically, being susceptible to exacerbated forms of inflammation, which leads to a fatal “cytokine storm”. Interestingly, some species of bats that are natural reservoirs of zoonotic viruses, including SARS-CoV-2, possess an IFN-based antiviral inflammatory response perpetually activated but do not show any sign of disease or cytokine storm. This is possible because bats present a constitutive HSR that is by far (hundreds of times) more intense and rapid than that of human, being associated with a high core temperature. Similarly in humans, fever is a physiological inducer of HSR while antipyretics, which block the initial phase of inflammation, impair the resolution phase of inflammation through the HSR. These findings offer a rationale for the reevaluation of patient care and fever reduction in SARS, including COVID-19.

Insufficient social distancing may contribute to COVID-19 outbreak: The case of Ijuí city in Brazil

“…male, older, and with existing cardiovascular disease) may be related to an impaired immune-metabolism stress response. Thus, these subjects cannot resolve virus-induced inflammatory bursts physiologically and are susceptible to exacerbated forms of inflammation [ 52 ], leading to a fatal “cytokine storm” [ 53 , 54 ]. Thus, in future studies it is necessary to examine adherence to protective social distancing behaviors together with the presence of comorbidities [ 3 , 55 ].…”

Plasma heat shock protein response to euglycemia in type 2 diabetes

“…First, since it has been described that diabetic and obese subjects, as well as menopausal women have a poor heat shock response (low ability to increase HSP synthesis or release these proteins into the bloodstream), the reduced ability to produce a heat shock response may be reflected in the results presented here. 50 Furthermore, it has been described that the duration of diabetes and the sum of comorbidities (obesity plus diabetes) show higher levels of extracellular HSPs (higher blood concentrations); 26 51 therefore, these subjects may not respond with new HSP release after a glycemic “challenge.” Second, the change in blood glucose in this study was within the clinically relevant range anticipated in normal diabetes regulation and therefore, at most, a modest “glycemic” challenge, or, indeed, could be considered as not a challenge at all but rather a return to an optimal homeostatic glycemic state.…”

Insufficient social distancing may be related to COVID-19 outbreak: the case of Ijuí city in Brazil

“…The increased risk of this profile (male, older and cardiovascular disease subject) may be related to an impaired immune-metabolism cell stress response. Thus, these subjects cannot resolve virus-induced inflammatory burst physiologically (since there is no medicine) being susceptible to exacerbated forms of inflammation [34], which leads to a fatal “cytokine storm” [35,36]. Thus, it is necessary to observe in future studies the adherence to a protective behavior linked to social distancing associated with the presence of comorbidities [3,37].…”