Improved control of SARS-CoV-2 by treatment with nucleocapsid-specific monoclonal antibody

The SARS-CoV-2 spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARSCoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific monoclonal antibody (mAb) exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated antibodydependent cellular cytotoxicity (ADCC) against infected cells. These findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based monoclonal antibody therapies to treat COVID-19

Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein

IntroductionMany people with long COVID symptoms suffer from debilitating neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Although symptoms of Neuro-PASC are widely documented, it is still unclear whether PASC symptoms impact virus-specific immune responses. Therefore, we examined T cell and antibody responses to SARS-CoV-2 Nucleocapsid protein to identify activation signatures distinguishing Neuro-PASC patients from healthy COVID convalescents.ResultsWe report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated CD4+ T cell responses and diminished CD8+ memory T cell activation toward the C-terminal region of SARS-CoV-2 Nucleocapsid protein when examined both functionally and using TCR sequencing. CD8+ T cell production of IL-6 correlated with increased plasma IL-6 levels as well as heightened severity of neurologic symptoms, including pain. Elevated plasma immunoregulatory and reduced pro-inflammatory and antiviral response signatures were evident in Neuro-PASC patients compared with COVID convalescent controls without lasting symptoms, correlating with worse neurocognitive dysfunction.DiscussionWe conclude that these data provide new insight into the impact of virus-specific cellular immunity on the pathogenesis of long COVID and pave the way for the rational design of predictive biomarkers and therapeutic interventions

The Commonly Used Anesthetic Propofol Dramatically Increases Host Susceptibility to Microbial Infection

Hospital peri-operative infections remain a major health concern, with surgery representing a leading cause of nosocomial infections. Anesthetics modulate host immune responses, but it has been difficult to separate the variable of surgery from anesthesia administration when analyzing infection rates. Here, the well-studied bacterial pathogen Listeria monocytogenes (LM) was used to assess the impact of a surgical anesthetic on host infection susceptibility. Brief sedation with propofol was sufficient to increase the bacterial burdens of LM in mouse target organs by 10,000-fold following both oral and intravenous routes of infection. Increased host susceptibility to oral infection with LM was dependent on heightened bacterial translocation across the intestinal barrier, but not through intestinal epithelial cells. This indicated that propofol increases LM translocation through alternate portals of entry. Propofol treatment did not alter LM invasion or replication within host cells in culture, disrupt tight junction integrity in Caco-2 intestinal epithelial cells, or decrease the efficacy of LM killing in primary murine macrophages. Though sedation with propofol is brief due to its short half-life, animals remained highly susceptible to infection even 96 hours after recovery from sedation. Though the alternate anesthetics sodium pentobarbital and ketamine increased the susceptibility of mice to oral infection with LM, they did not affect susceptibility to intravenous systemic infection with LM, unlike propofol. Additionally, anesthetized animals infected with LM displayed more severe organ pathology in livers, spleens, and intestines. Propofol treatment altered serum cytokine and chemokine levels throughout infection, with particularly striking effects on IFN-γ, MCP-1, IL-10 and TNF-α. Concurrently, fewer differentiated macrophages and TNF and iNOS producing dendritic cells, both important in clearing LM, were evident in animals treated with propofol. Finally, animals sedated with propofol showed heightened susceptibility to 2 methicillin-resistant Staphylococcus aureus, Salmonella enterica serovar Typhimurium, and Streptococcus pyogenes as evidenced by increased bacterial burdens in target organs. These data indicate that anesthetization with propofol severely compromises host resistance to infection, an observation that has potentially profound implications for surgical outcomes and, ultimately, patient survival

Role of Group 1 CD1-Restricted T Cells in Infectious Disease

The evolutionarily conserved CD1 family of antigen-presenting molecules presents lipid antigens rather than peptide antigens to T cells. CD1 molecules, unlike classical MHC molecules, display limited polymorphism, making CD1-restricted lipid antigens attractive vaccine targets that could be recognized in a genetically diverse human population. Group 1 CD1 (CD1a, CD1b, and CD1c)-restricted T cells have been implicated to play critical roles in a variety of autoimmune and infectious diseases. In this review, we summarize current knowledge and recent discoveries on the development of group 1 CD1-restricted T cells and their function in different infection models. In particular, we focus on (1) newly identified microbial and self–lipid antigens, (2) kinetics, phenotype, and unique properties of group 1 CD1-restricted T cells during infection, and (3) the similarities of group 1 CD1-restricted T cells to the closely related group 2 CD1-restricted T cells

Data_Sheet_1_Case report: Treatment of long COVID with a SARS-CoV-2 antiviral and IL-6 blockade in a patient with rheumatoid arthritis and SARS-CoV-2 antigen persistence.pdf

IntroductionLong COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC) in ∼30% of all infected individuals. Here, we present a case of PASC in a patient with rheumatoid arthritis characterized by viral persistence in the nasopharynx for 6 months after acute infection. We demonstrate transient disappearance of antigen persistence and decreased antiviral and autoimmune T cell responses after nirmatrelvir/ritonavir and tocilizumab treatment.Case presentationA 37-year-old female with a 7-year history of rheumatoid arthritis enrolled in a COVID-19 research study was found to continuously test SARS-CoV-2 antigen positive in the nasopharynx for 6 months after acute infection. She simultaneously presented with new-onset PASC symptoms including chronic occipital headache and periods of intense fatigue 8 weeks after acute infection. The patient was prescribed nirmatrelvir/ritonavir to treat SARS-CoV-2 persistence at 3.5 months post-acute infection and observed a reduction in PASC symptoms 3 weeks after completing antiviral treatment. After resurgence of PASC symptoms, she stopped treatment with tocilizumab for rheumatoid arthritis to attempt complete SARS-CoV-2 viral clearance. The severity of the patient’s PASC symptoms subsequently increased, and she developed new-onset brain fog in addition to previous symptoms, which resolved after resumption of tocilizumab treatment. Assessment of adaptive immune responses demonstrated that nirmatrelvir/ritonavir and tocilizumab treatment decreased antiviral and autoreactive T cell activation. After resuming tocilizumab treatment, the patient’s PASC symptoms were significantly reduced, but nasopharyngeal antigen positivity remained.ConclusionThese data suggest that nirmatrelvir/ritonavir should be considered in the treatment of PASC in patients who have SARS-CoV-2 antigen persistence, though care must be taken to monitor the patient for symptom resurgence or viral reactivation. In addition, the IL-6 inhibitor tocilizumab may ameliorate PASC symptoms in patients with persistent headache, fatigue, and brain fog.</p

Propofol Increases Host Susceptibility to Microbial Infection by Reducing Subpopulations of Mature Immune Effector Cells at Sites of Infection

<div><p>Anesthetics are known to modulate host immune responses, but separating the variables of surgery from anesthesia when analyzing hospital acquired infections is often difficult. Here, the bacterial pathogen <i>Listeria monocytogenes</i> (<i>Lm</i>) was used to assess the impact of the common anesthetic propofol on host susceptibility to infection. Brief sedation of mice with physiologically relevant concentrations of propofol increased bacterial burdens in target organs by more than 10,000-fold relative to infected control animals. The adverse effects of propofol sedation on immune clearance of <i>Lm</i> persisted after recovery from sedation, as animals given the drug remained susceptible to infection for days following anesthesia. In contrast to propofol, sedation with alternative anesthetics such as ketamine/xylazine or pentobarbital did not increase susceptibility to systemic <i>Lm</i> infection. Propofol altered systemic cytokine and chemokine expression during infection, and prevented effective bacterial clearance by inhibiting the recruitment and/or activity of immune effector cells at sites of infection. Propofol exposure induced a marked reduction in marginal zone macrophages in the spleens of <i>Lm</i> infected mice, resulting in bacterial dissemination into deep tissue. Propofol also significantly increased mouse kidney abscess formation following infection with the common nosocomial pathogen <i>Staphylococcus aureus</i>. Taken together, these data indicate that even brief exposure to propofol severely compromises host resistance to microbial infection for days after recovery from sedation.</p></div

Propofol increases host susceptibility to <i>S</i>. <i>aureus</i> infection.

<p>(a). Mice were intravenously infected with 1 x 10⁶ CFU <i>S</i>. <i>aureus</i> USA300 ± propofol and kidneys were isolated at 14 days post-infection. Arrows: abscess formation. (b). Levels of inflammation and necrosis in the kidney expressed as percentage of histological sections ± SEM, with 5–6 animals per group. (c). Mice were infected with 1 x 10⁶ CFU <i>S</i>. <i>aureus</i> USA300 ± propofol and sacrificed at 7 days post-infection. Kidneys were fixed and processed for H&E staining. Propofol increased inflammation, caused the loss of kidney compartmentalization, and increased the number and size of abscesses. Left: images from 2 mice infected with <i>S</i>. <i>aureus</i> USA300 without propofol. Right: images from 2 mice infected with <i>S</i>. <i>aureus</i> USA300 with propofol. Top: 2x magnification; bottom: 20x magnification.</p

Model of the effects of propofol on host susceptibility to microbial infection.

<p>Propofol binds to the GABA-A receptor in the CNS to induce anesthesia. Upon infection, propofol increases bacterial translocation across physiological barriers and inhibits immune clearance of bacteria from target organs. Propofol is speculated to mediate immunosuppression through the action of metabolic intermediates produced in the liver that may bind to alternative receptors and alter patterns of cytokine and chemokine signaling in response to infection. Propofol sedation inhibits the recruitment and/or activity of immune effector cells at sites of infection, thereby increasing bacterial replication and organ pathology.</p