Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection.

Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.

Membrane heist: Coronavirus host membrane remodeling during replication.

The ongoing pandemic of COVID-19 (Coronavirus Disease-2019), a respiratory disease caused by the novel coronavirus strain, SARS-CoV-2, has affected more than 42 million people already, with more than one million deaths worldwide (as of October 25, 2020). We are in urgent need of therapeutic interventions that target the host-virus interface, which requires a molecular understanding of the SARS-CoV-2 life-cycle. Like other positive-sense RNA viruses, coronaviruses remodel intracellular membranes to form specialized viral replication compartments, including double-membrane vesicles (DMVs), where viral RNA genome replication takes place. Here we review the current knowledge of the structure, lipid composition, function, and biogenesis of coronavirus-induced DMVs, highlighting the druggable viral and cellular factors that are involved in the formation and function of DMVs.

How SARS-CoV-2 (COVID-19) spreads within infected hosts - what we know so far.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19), belongs to the betacoronavirus genus and shares high homology to the severe acute respiratory syndrome coronavirus (SARS-CoV) that emerged in 2003. These are highly transmissible and pathogenic viruses which very likely originated in bats. SARS-CoV-2 uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as SARS-CoV, and spreads primarily through the respiratory tract. Although several trials for vaccine development are currently underway, investigations into the virology of SARS-CoV-2 to understand the fundamental biology of the infectious cycle and the associated immunopathology underlying the clinical manifestations of COVID-19 are crucial for identification and rational design of effective therapies. This review provides an overview of how SARS-CoV-2 infects and spreads within human hosts with specific emphasis on key aspects of its lifecycle, tropism and immunopathological features.

Manipulation of autophagy by (+) RNA viruses.

Autophagy is an evolutionarily conserved process central to host metabolism. Among its major functions are conservation of energy during starvation, recycling organelles, and turnover of long-lived proteins. Besides, autophagy plays a critical role in removing intracellular pathogens and very likely represents a primordial intrinsic cellular defence mechanism. More recent findings indicate that it has not only retained its ability to degrade intracellular pathogens, but also functions to augment and fine tune antiviral immune responses. Interestingly, viruses have also co-evolved strategies to manipulate this pathway and use it to their advantage. Particularly intriguing is infection-dependent activation of autophagy with positive stranded (+)RNA virus infections, which benefit from the pathway without succumbing to lysosomal degradation. In this review we summarise recent data on viral manipulation of autophagy, with a particular emphasis on +RNA viruses and highlight key unanswered questions in the field that we believe merit further attention.