Pro-Viral and Anti-Viral Roles of the RNA-Binding Protein G3BP1.

Viruses depend on host cellular resources to replicate. Interaction between viral and host proteins is essential for the pathogens to ward off immune responses as well as for virus propagation within the infected cells. While different viruses employ unique strategies to interact with diverse sets of host proteins, the multifunctional RNA-binding protein G3BP1 is one of the common targets for many viruses. G3BP1 controls several key cellular processes, including mRNA stability, translation, and immune responses. G3BP1 also serves as the central hub for the protein-protein and protein-RNA interactions within a class of biomolecular condensates called stress granules (SGs) during stress conditions, including viral infection. Increasing evidence suggests that viruses utilize distinct strategies to modulate G3BP1 function-either by degradation, sequestration, or redistribution-and control the viral life cycle positively and negatively. In this review, we summarize the pro-viral and anti-viral roles of G3BP1 during infection among different viral families.

The Integral Membrane Protein ZMPSTE24 Protects Cells from SARS-CoV-2 Spike-Mediated Pseudovirus Infection and Syncytia Formation.

COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on global public health, emphasizing the importance of understanding innate immune mechanisms and cellular restriction factors that cells can harness to fight viral infections. The multimembrane-spanning zinc metalloprotease ZMPSTE24 is one such restriction factor. ZMPSTE24 has a well-characterized proteolytic role in the maturation of prelamin A, precursor of the nuclear scaffold protein lamin A. An apparently unrelated role for ZMPSTE24 in viral defense involves its interaction with the interferon-inducible membrane proteins (IFITMs), which block virus-host cell fusion by rigidifying cellular membranes and thereby prevent viral infection. ZMPSTE24, like the IFITMs, defends cells against a broad spectrum of enveloped viruses. However, its ability to protect against coronaviruses has never been examined. Here, we show that overexpression of ZMPSTE24 reduces the efficiency of cellular infection by SARS-CoV-2 Spike-pseudotyped lentivirus and that genetic knockout or small interfering RNA-mediated knockdown of endogenous ZMPSTE24 enhances infectivity. We further demonstrate a protective role for ZMPSTE24 in a Spike-ACE2-dependent cell-cell fusion assay. In both assays, a catalytic dead version of ZMPSTE24 is equally as protective as the wild-type protein, indicating that ZMPSTE24's proteolytic activity is not required for defense against SARS-CoV-2. Finally, we demonstrate by plaque assays that Zmpste24-/- mouse cells show enhanced infection by a genuine coronavirus, mouse hepatitis virus (MHV). This study extends the range of viral protection afforded by ZMPSTE24 to include coronaviruses and suggests that targeting ZMPSTE24's mechanism of viral defense could have therapeutic benefit. IMPORTANCE The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has underscored the importance of understanding intrinsic cellular components that can be harnessed as the cell's first line of defense to fight against viral infection. Our paper focuses on one such protein, the integral membrane protease ZMPSTE24, which interacts with interferon-inducible transmembrane proteins (IFITMs). IFITMs interfere with virus entry by inhibiting fusion between viral and host cell membranes, and ZMPSTE24 appears to contribute to this inhibitory activity. ZMPSTE24 has been shown to defend cells against several, but not all, enveloped viruses. In this study, we extend ZMPSTE24's reach to include coronaviruses, by showing that ZMPSTE24 protects cells from SARS-CoV-2 pseudovirus infection, Spike protein-mediated cell-cell fusion, and infection by the mouse coronavirus MHV. This work lays the groundwork for further studies to decipher the mechanistic role of ZMPSTE24 in blocking the entry of SARS-CoV-2 and other viruses into cells.

Why does viral RNA sometimes persist after recovery from acute infections?

DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?

B-Cell Responses in Hospitalized Severe Acute Respiratory Syndrome Coronavirus 2-Infected Children With and Without Multisystem Inflammatory Syndrome.

Multisystem inflammatory syndrome in children (MIS-C) can complicate infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but differences in the immune responses during MIS-C compared to coronavirus disease 2019 (COVID-19) are poorly understood. We longitudinally compared the amounts and avidity of plasma anti-nucleocapsid (N) and spike (S) antibodies, phenotypes of B cells, and numbers of virus-specific antibody-secreting cells in circulation of children hospitalized with COVID-19 (n = 10) and with MIS-C (n = 12). N-specific immunoglobulin G (IgG) was higher early after presentation for MIS-C than COVID-19 patients and avidity of N- and S-specific IgG at presentation did not mature further during follow-up as it did for COVID-19. Both groups had waning proportions of B cells in circulation and decreasing but sustained production of virus-specific antibody-secreting cells for months. Overall, B-cell responses were similar, but those with MIS-C demonstrated a more mature antibody response at presentation compared to COVID-19, suggesting a postinfectious entity.

Continued Virus-Specific Antibody-Secreting Cell Production, Avidity Maturation and B Cell Evolution in Patients Hospitalized with COVID-19.

Understanding the development and sustainability of the virus-specific protective immune response to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains incomplete with respect to the appearance and disappearance of virus-specific antibody-secreting cells (ASCs) in circulation. Therefore, we performed cross-sectional and longitudinal analyses of peripheral blood mononuclear cells and plasma collected from 55 hospitalized patients up to 4 months after onset of COVID-19 symptoms. Spike (S)- and nucleocapsid (N)-specific IgM and IgG ASCs appeared within 2 weeks accompanied by flow cytometry increases in double negative plasmablasts consistent with a rapid extrafollicular B cell response. Total and virus-specific IgM and IgG ASCs peaked at 3-4 weeks and were still being produced at 3-4 months accompanied by increasing antibody avidity consistent with a slower germinal center B cell response. N-specific ASCs were produced for longer than S-specific ASCs and avidity maturation was greater for antibody to N than S. Patients with more severe disease produced more S-specific IgM and IgG ASCs than those with mild disease and had higher levels of N- and S-specific antibody. Women had more B cells in circulation than men and produced more S-specific IgA and IgG and N-specific IgG ASCs. Flow cytometry analysis of B cell phenotypes showed an increase in circulating B cells at 4-6 weeks with decreased percentages of switched and unswitched memory B cells. These data indicate ongoing antigen-specific stimulation, maturation, and production of ASCs for several months after onset of symptoms in patients hospitalized with COVID-19.

The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses.

Emerging and re-emerging viral diseases pose continuous public health threats, and effective control requires a combination of non-pharmacologic interventions, treatment with antivirals, and prevention with vaccines. The COVID-19 pandemic has demonstrated that the world was least prepared to provide effective treatments. This lack of preparedness has been due, in large part, to a lack of investment in developing a diverse portfolio of antiviral agents, particularly those ready to combat viruses of pandemic potential. Here, we focus on a drug target called macrodomain that is critical for the replication and pathogenesis of alphaviruses and coronaviruses. Some mutations in alphavirus and coronaviral macrodomains are not tolerated for virus replication. In addition, the coronavirus macrodomain suppresses host interferon responses. Therefore, macrodomain inhibitors have the potential to block virus replication and restore the host's protective interferon response. Viral macrodomains offer an attractive antiviral target for developing direct acting antivirals because they are highly conserved and have a structurally well-defined (druggable) binding pocket. Given that this target is distinct from the existing RNA polymerase and protease targets, a macrodomain inhibitor may complement current approaches, pre-empt the threat of resistance and offer opportunities to develop combination therapies for combating COVID-19 and future viral threats.

US–Japan Cooperative Medical Sciences Program’s Virtual Workshop on COVID-19

The US–Japan Cooperative Medical Sciences Program, a 56-year-old bilateral program, has convened the International Conferences on Emerging Infectious Diseases in the Pacific Rim in different countries in the Asia–Pacific region since 1996 (1,2). Because of the ongoing pandemic, the annual conference could not convene in person. In a presentation that outlined the serologic characteristic of SARS-CoV-2 infection and the latest technologic advances aimed at increasing sensitivity and specificity of viral infection diagnostics, the speaker noted the importance of considering the disease prevalence and the influence of factors, such as age and disease severity, among different groups within a population in developing assay platforms, and a need for the development of SARS-CoV-2–specific IgA diagnostic tests. Google Scholar Yohei Doi, Ken Ishii, Akira Nishizono, Asuka Nanbo, Shuzo Urata, Ichiro Kurane, Jules Carl Celebrado, John Philip Depatillo, Zymar Bandola, Diane E. Griffin, Eun-Chung Park, David McDonald, Kristina Lu, K. Gayle Bernabe , and Gray Handley Fujita Health University School of Medicine, Toyoake, Japan (Y. Doi);University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA (Y. Doi);University of Tokyo, Tokyo, Japan (K. Ishii);Oita University Faculty of Medicine, Oita, Japan (A. Nishizono);National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki, Japan (A. Nanbo, S. Urata);National Institute of Infectious Diseases, Tokyo (I. Kurane);Department of Science and Technology, Manila, Philippines (J.C. Celebrado, J.P. Depatillo, Z. Bandola);Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA (D.E. Griffin);National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA (E.-C.

U.S.-Japan cooperative medical sciences program: 22nd International Conference on Emerging Infectious Diseases in the Pacific Rim.

This review summarizes the presentations given at the 22nd International conference on Emerging Infectious Diseases in the Pacific Rim. The purpose of this annual meeting is to foster international collaborations and address important public health issues in the Asia-Pacific region. This meeting was held in Bangkok in February 2020 and focused on emerging virus infections. Unexpectedly, the SARS-CoV-2 pandemic was in the initial stages leading to a special session on COVID-19 in addition to talks on dengue, influenza, hepatitis, AIDS, Zika, chikungunya, rabies, cervical cancer and nasopharyngeal carcinoma.

Acute RNA Viral Encephalomyelitis and the Role of Antibodies in the Central Nervous System

Acute RNA viral encephalomyelitis is a serious complication of numerous virus infections. Antibodies in the cerebral spinal fluid (CSF) are correlated to better outcomes, and there is substantive evidence of antibody secreting cells (ASCs) entering the central nervous system (CNS) and contributing to resolution of infection. Here, we review the RNA viruses known to cause acute viral encephalomyelitis with mechanisms of control that require antibody or ASCs. We compile the cytokines, chemokines, and surface receptors associated with ASC recruitment to the CNS after infection and compare known antibody-mediated mechanisms as well as potential noncytolytic mechanisms for virus control. These non-canonical functions of antibodies may be employed in the CNS to protect precious non-renewable neurons. Understanding the immune-specialized zone of the CNS is essential for the development of effective treatments for acute encephalomyelitis caused by RNA viruses.

Are T cells helpful for COVID-19: the relationship between response and risk.

The disease spectrum of coronavirus disease 2019 (COVID-19) ranges from no symptoms to multisystem failure and death. Characterization of virus-specific immune responses to severe acute respiratory coronavirus 2 (SARS-CoV-2) is key to understanding disease pathogenesis, but few studies have evaluated T cell immunity. In this issue of the JCI, Sattler and Angermair et al. sampled blood from subjects with COVID-19 and analyzed the activation and function of virus antigen-specific CD4+ T cells. T cells that failed to respond to peptides from the membrane, spike, or nucleocapsid proteins were more common in subjects who died. In those whose T cells had the capacity to respond, older patients with comorbidity had larger numbers of activated T cells compared with patients who had fewer risk factors, but these cells showed impaired IFN-γ production. This cross-sectional study relates activated T cell responses to patient risk factors and outcome. However, T cell response trajectory over the disease course remains an open question.