Phase separation in viral infections.

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

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Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

Coronaviruses are the etiologic agents of several diseases. Coronaviruses of critical medical importance are characterized by highly inflammatory pathophysiology, involving severe pulmonary impairment and infection of multiple cell types within the body. Here, we discuss the interplay between coronaviruses and autophagy regarding virus life cycle, cell resistance, and inflammation, highlighting distinct mechanisms by which autophagy restrains inflammatory responses, especially those involved in coronavirus pathogenesis. We also address different autophagy modulators available and the rationale for drug repurposing as an attractive adjunctive therapy. We focused on pharmaceuticals being tested in clinical trials with distinct mechanisms but with autophagy as a common target. These autophagy modulators act in cell resistance to virus infection and immunomodulation, providing a double-strike to prevent or treat severe disease development and death from coronaviruses diseases.

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Autophagy Modulators in Coronavirus Diseases: A Double Strike in Viral Burden and Inflammation

Abstract The exposure of organisms and cells to unfavorable conditions such as increased temperature, antibiotics, reactive oxygen species, and viruses could lead to protein misfolding and cell death. The increased production of proteins such as heat shock proteins (HSPs) and polyamines has been linked to protein misfolding sequestration, thus maintaining, enhancing, and regulating the cellular system. For example, heat shock protein 40 (Hsp40) works hand in hand with Hsp70 and Hsp90 to successfully assist the newly synthesized proteins in folding properly. On the other hand, polyamines such as putrescine, spermidine, and spermine have been widely studied and reported to keep cells viable under harsh conditions, which are also involved in cell proliferation, differentiation, and growth. Polyamines are found in all living organisms, including humans and viruses. Some organisms have developed a mechanism to hijack mammalian host cell machinery for their benefit like viruses need polyamines for infection. Therefore, the role of HSPs and polyamines in SARS-CoV-2 (COVID-19) viral infection, how these molecules could delay the effectiveness of the current treatment in the market, and how COVID-19 relies on the host molecules for its successful infection are reviewed.

The capture of host cell’s resources: The role of heat shock proteins and polyamines in SARS-COV-2 (COVID-19) pathway to viral infection

Identification of viral receptors has always been the research hot spot in virus research field as receptor functions at the first stage of viral infection, which can be designed as efficient antiviral drug targets. GCRV-II, the causative agent of the grass carp epidemic hemorrhagic disease, has caused tremendous losses in grass carp culture in China. ABSTRACT The frequent outbreak of grass carp hemorrhagic disease caused by grass carp reovirus (GCRV), especially the mainly prevalent type II GCRV (GCRV-II), has seriously affected the grass carp culture in China. However, its pathogenic mechanism is still far from clear. In this study, the GCRV-II outer capsid protein VP35 was used as bait to capture interacting partners from Ctenopharyngon idellus kidney (CIK) cells, and heat shock protein 90 (Hsp90) was selected and confirmed interacting with VP35 through the C-terminal domain of Hsp90. Knockdown of Hsp90 or inhibition of Hsp90 activity suppressed GCRV-II proliferation, demonstrating that Hsp90 is an essential factor for GCRV-II proliferation. The confocal microscopy and flow cytometry showed that Hsp90 localized at both membrane and cytoplasm of CIK cells. The entry of GCRV-II into CIK cells was efficiently blocked by incubating the cells with Hsp90 antibody or by pretreating the virus with recombinant Hsp90 protein. Whereas overexpression of Hsp90 in CIK cells, grass carp ovary (GCO) cells, or 293T cells promoted GCRV-II entry, indicating that the membrane Hsp90 functions as a receptor of GCRV-II. Furthermore, Hsp90 interacted with clathrin and mediated GCRV-II entry into CIK cells through clathrin endocytosis pathway. In addition, we found that the cytoplasmic Hsp90 acted as a chaperone of VP35 because inhibition of Hsp90 activity enhanced VP35 polyubiquitination and degraded VP35 through the proteasome pathway. Collectively, our data suggest that Hsp90 functions both as a receptor for GCRV-II entry and a chaperone for the maturation of GCRV-II VP35, thus ensuring efficient proliferation of GCRV-II. IMPORTANCE Identification of viral receptors has always been the research hot spot in virus research field as receptor functions at the first stage of viral infection, which can be designed as efficient antiviral drug targets. GCRV-II, the causative agent of the grass carp epidemic hemorrhagic disease, has caused tremendous losses in grass carp culture in China. To date, the receptor of GCRV-II remains unknown. This study focused on identifying cellular receptor interacting with the GCRV-II outer capsid protein VP35, studying the effects of their interaction on GCRV-II proliferation, and revealing the underlying mechanisms. We demonstrated that Hsp90 acts both as a receptor of GCRV-II by interacting with VP35 and as a chaperone for the maturation of VP35, thus ensuring efficient proliferation of GCRV-II. Our data provide important insights into the role of Hsp90 in GCRV-II life cycle, which will help understand the mechanism of reovirus infection.

Hsp90 Regulates GCRV-II Proliferation by Interacting with VP35 as Its Receptor and Chaperone

Heat shock proteins (HSPs) are a large group of chaperones found in most eukaryotes and bacteria. They are responsible for the correct protein folding, protection of the cell against stressors, presenting immune and inflammatory cytokines; furthermore, they are important factors in regulating cell differentiation, survival and death. Although the biological function of HSPs is to maintain cell homeostasis, some of them can be used by viruses both to fold their proteins and increase the chances of survival in unfavorable host conditions. Folding viral proteins as well as replicating many different viruses are carried out by, among others, proteins from the HSP70 and HSP90 families. In some cases, the HSP70 family proteins directly interact with viral polymerase to enhance viral replication or they can facilitate the formation of a viral replication complex and/or maintain the stability of complex proteins. It is known that HSP90 is important for the expression of viral genes at both the transcriptional and the translational levels. Both of these HSPs can form a complex with HSP90 and, consequently, facilitate the entry of the virus into the cell. Current studies have shown the biological significance of HSPs in the course of infection SARS-CoV-2. A comprehensive understanding of chaperone use during viral infection will provide new insight into viral replication mechanisms and therapeutic potential. The aim of this study is to describe the molecular basis of HSP70 and HSP90 participation in some viral infections and the potential use of these proteins in antiviral therapy.

Role of Heat Shock Proteins (HSP70 and HSP90) in Viral Infection.

Gluten to mieszanina wielu pojedynczych, powiązanych bialek, ktore tworzą material magazynowy w pszenicy. Są to glownie gliadyny monomeryczne i gluteniny polimeryczne tworzące ze sobą kompleksy, stabilizowane mostkami dwusiarczkowymi, dlatego tez tworząca je cysteina odgrywa bardzo wazną role w budowie i funkcjonalności glutenu. W artykule porownano cechy wybranych zboz, takie jak zawartośc poszczegolnych skladnikow pokarmowych, wymagania glebowo-klimatyczne oraz wlaściwości stosowane w produkcji zywności. Obecnośc glutenu w zywności jest problemem z punktu widzenia jej wplywu na organizm czlowieka. Oczekuje sie, ze skupienie badan na modyfikacji genomu pszenicy doprowadzi do otrzymania odmiany pszenicy o nietoksycznych wlaściwościach dla osob cierpiących na celiakie i rozne formy nietolerancji bialka glutenu. Specyficzne sekwencje znalezione w bialkach pszenicy wiązą sie z przeciwcialami IgE, powodując roznorodne objawy chorobowe. W artykule omowiono kryteria diagnostyczne celiakii i alergii na pszenice oraz wplyw odstawienia glutenu na kliniczne objawy celiakii.

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Gluten and gluten-dependent diseases

Reumatoidalne zapalenie stawow (RZS) jest jedną z najczestszych chorob autoimmunologicznych tkanki lącznej. Pierwsze objawy choroby pojawiają sie zwykle miedzy 30 a 50 rokiem zycia i obejmują przewlekly proces zapalny, ktory powoduje postepujące niszczenie ukladu kostno-stawowego i zmiany narządowe. Etiologia RZS nie jest dotychczas dostatecznie poznana, a zarowno czynniki genetyczne, jak i środowiskowe odgrywają role w patogenezie RZS. Rozpoznanie opiera sie na kryteriach American Collegium of Reumathology (ACR) oraz European League Against Rheumatism (EULAR) z 2010 roku. Wśrod metod fizykoterapii stosowanych w leczeniu RZS szczegolną role odgrywa krioterapia (kriostymulacja). Zgodnie z wytycznymi Panelu Ottawa kinezyterapia czynnościowa powinna odgrywac szczegolną role u chorych na RZS, ktory ma na celu przywrocenie wzorcow ruchowych najbardziej zblizonych do fizjologii. Stosując kinezyterapie u chorych na RZS, nalezy monitorowac przebieg procesow kompensacyjnych. Brak nadzoru lekarza i fizjoterapeuty nad powyzszym procesem prowadzi do przeciązenia, a nastepnie deformacji ukladu mieśniowo-szkieletowego.

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Alicja Lalko

Papers

Role of Heat Shock Proteins (HSP70 and HSP90) in Viral Infection.

Gluten and gluten-dependent diseases

Diagnostics and physiotherapy in rheumatoid arthritis