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The nucleocapsid (N) protein plays critical roles in coronavirus genome transcription and packaging, representing a key target for the development of novel antivirals, and for which structural information on ligand binding is scarce. We used a novel fluorescence polarization assay to identify small molecules that disrupt the binding of the N protein to a target RNA derived from the SARS-CoV-2 genome packaging signal. Several phenolic compounds, including L-chicoric acid (CA), were identified as high-affinity N-protein ligands. The binding of CA to the N protein was confirmed by isothermal titration calorimetry, 1H-STD and 15N-HSQC NMR, and by the crystal structure of CA bound to the N protein C-terminal domain (CTD), further revealing a new modulatory site in the SARS-CoV-2 N protein. Moreover, CA reduced SARS-CoV-2 replication in cell cultures. These data thus open venues for the development of new antivirals targeting the N protein, an essential and yet underexplored coronavirus target. [ABSTRACT FROM AUTHOR]

Currently, there are no evidence-based treatment options for long COVID-19, and it is known that SARS-CoV-2 can persist in part of the infected patients, especially those with immunosuppression. Since there is a robust secretion of SARS-CoV-2-specific highly-neutralizing IgA antibodies in breast milk, and because this immunoglobulin plays an essential role against respiratory virus infection in mucosa cells, being, in addition, more potent in neutralizing SARS-CoV-2 than IgG, here we report the clinical course of an NFκB-deficient patient chronically infected with the SARS-CoV-2 Gamma variant, who, after a non-full effective treatment with plasma infusion, received breast milk from a vaccinated mother by oral route as treatment for COVID-19. After such treatment, the symptoms improved, and the patient was systematically tested negative for SARS-CoV-2. Thus, we hypothesize that IgA and IgG secreted antibodies present in breast milk could be useful to treat persistent SARS-CoV-2 infection in immunodeficient patients. [ABSTRACT FROM AUTHOR]

Background: Common variable immunodeficiency is the most prevalent symptomatic primary immunodeficiency in adults. Affected patients fail to mount an appropriate humoral response against community acquired infectious diseases and recent reports have provided data supporting the increased susceptibility of these patients to severe SARS-CoV-2 infections. In this context, the infusion of COVID-19 convalescent plasma could represent an effective therapeutic strategy. Case presentation: 25-year old woman diagnosed with common variable immunodeficiency in 2013, developed severe COVID-19 that rapidly progressed to pneumonia presenting with multiple bilateral lung opacities that were both central and peripheral and presented as ground-glass and consolidation types involving all lobes, bilaterally. As blood oxygen saturation decayed and lung abnormalities were not responsive to large spectrum antibiotics and corticosteroids, patient was placed on mechanical ventilation and compassionate-use of approved COVID-19 convalescent donor plasma was introduced. The patient presented a rapid response to the approach and mechanical ventilation could be interrupted 24 h after first dose of COVID-19 convalescent donor plasma. As a whole, the patient received four doses of 200 mL convalescent plasma during a period of 6 days. There was rapid improvement of clinical status, with interruption of supplemental oxygen therapy after 6 days and reduction of lung abnormalities as evidence by sequential computed tomography scans. Conclusions: This is a single patient report that adds to other few reports on common variable immunodeficiency and agammaglobulinemia, suggesting that COVID-19 convalescent donor plasma could be a valuable therapeutic approach to treat patients affected by dysgammaglobulinemias and presenting severe COVID-19. [ABSTRACT FROM AUTHOR]

Type B coxsackievirus (CVB) is a common cause of acute and chronic myocarditis, meningitis and pancreatitis, often leading to heart failure and pancreatic deficiency. The polarization of CD4+ T lymphocytes and their cytokine milieu are key factors in the outcome of CVB-induced diseases. Thus, sensing the virus and driving the adaptive immune response are essential for the establishment of a protective immune response. TLR3 is a crucial virus recognition receptor that confers the host with resistance to CVB infection. In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86 to a less degree than WT cells. Instead, they up-regulated the inhibitory molecule PD-L1 and secreted considerably lower levels of TNF-α and IL-10 and a higher level of IL-23. T lymphocyte proliferation in co-culture with CVB3-infected dendritic cells was increased by TLR3-expressing DCs and other cells. Furthermore, in the absence of TLR3, the T lymphocyte response was shifted toward a Th17 profile, which was previously reported to be deleterious for the host. TLR3-deficient mice were very susceptible to CVB3 infection, with increased pancreatic injury and extensive inflammatory infiltrate in the heart that was associated with uncontrolled viral replication. Adoptive transfer of TLR3+ dendritic cells slightly improved the survival of TLR-deficient mice following CVB3 infection. Therefore, our findings highlight the importance of TLR3 signaling in DCs and in other cells to induce activation and polarization of the CD4+ T lymphocyte response toward a Th1 profile and consequently for a better outcome of CVB3 infection. These data provide new insight into the immune-mediated mechanisms by which CVBs are recognized and cleared in order to prevent the development of myocarditis and pancreatitis and may contribute to the design of therapies for enteroviral infections. [ABSTRACT FROM AUTHOR]