Requirement of Fc-Fc gamma receptor interaction for antibody-based protection against emerging virus infections

Identification of therapeutics against emerging and re-emerging viruses remains a continued priority that is only reinforced by the recent SARS-CoV-2 pandemic. Advances in monoclonal antibody (mAb) isolation, characterization, and production make it a viable option for rapid treatment development. While mAbs are traditionally screened and selected based on potency of neutralization in vitro, it is clear that additional factors contribute to the in vivo efficacy of a mAb beyond viral neutralization. These factors include interactions with Fc receptors (FcRs) and complement that can enhance neutralization, clearance of infected cells, opsonization of virions, and modulation of the innate and adaptive immune response. In this review, we discuss recent studies, primarily using mouse models, that identified a role for Fc-FcγR interactions for optimal antibody-based protection against emerging and re-emerging virus infections

Viral Replication, Persistence in Water and Genetic Characterization of Two Influenza A Viruses Isolated from Surface Lake Water

Water-borne transmission has been suggested as an important transmission mechanism for Influenza A (IA) viruses in wild duck populations; however, relatively few studies have attempted to detect IA viruses from aquatic habitats. Water-isolated viruses have rarely been genetically characterized and evaluation for persistence in water and infectivity in natural hosts has never been documented. In this study, we focused on two IA viruses (H3N8 and H4N6 subtypes) isolated from surface lake water in Minnesota, USA. We investigated the relative prevalence of the two virus subtypes in wild duck populations at the sampling site and their genetic relatedness to IA viruses isolated in wild waterbirds in North America. Viral persistence under different laboratory conditions (temperature and pH) and replication in experimentally infected Mallards (Anas platyrhynchos) were also characterized. Both viruses were the most prevalent subtype one year following their isolation in lake water. The viruses persisted in water for an extended time period at constant temperature (several weeks) but infectivity rapidly reduced under multiple freeze-thaw cycles. Furthermore, the two isolates efficiently replicated in Mallards. The complete genome characterization supported that these isolates originated from genetic reassortments with other IA viruses circulating in wild duck populations during the year of sampling. Based on phylogenetic analyses, we couldn't identify genetically similar viruses in duck populations in the years following their isolation from lake water. Our study supports the role for water-borne transmission for IA viruses but also highlights that additional field and experimental studies are required to support inter-annual persistence in aquatic habitats

Nasally delivered interferon-λ protects mice against infection by SARS-CoV-2 variants including Omicron

Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, variants with constellations of mutations in the spike gene jeopardize their efficacy. Accordingly, antiviral interventions that are resistant to further virus evolution are needed. The host-derived cytokine interferon lambda (IFN-λ) has been proposed as a possible treatment based on studies in human coronavirus 2019 (COVID-19) patients. Here, we show that IFN-λ protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1.529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally delivered IFN-λ2 limits infection of historical or variant SARS-CoV-2 strains in the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-λ is produced preferentially in epithelial cells and acts on radio-resistant cells to protect against SARS-CoV-2 infection. Thus, inhaled IFN-λ may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures

Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease

Epithelial cells are charged with protection at barrier sites, but whether this normally beneficial response might sometimes become dysfunctional still needs definition. Here, we recognized a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaced normal airspaces in a mouse model of progressive postviral lung disease due to the Sendai virus. Single-cell and lineage-tracing technologies identified a distinct subset of basal epithelial stem cells (basal ESCs) that extended into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset was selectively expanded by crossing a cell-growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that was independent of IL-33 receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupted the homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuated postviral disease in the lung based on the downregulation of remodeling and inflammation. Thus, we define a basal ESC strategy to deploy innate immune machinery that appears to overshoot the primordial goal of self-defense. Our findings reveal new targets to stratify and correct chronic and often deadly postviral disease

Potently neutralizing and protective human antibodies against SARS-CoV-2

The COVID-19 pandemic is a major threat to global health1 for which there are limited medical countermeasures2,3. Moreover, we currently lack a thorough understanding of mechanisms of humoral immunity4. From a larger panel of human monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein5, we identified several that exhibited potent neutralizing activity and fully blocked the receptor-binding domain of S (SRBD) from interacting with human ACE2 (hACE2). Competition-binding, structural, and functional studies allowed clustering of the mAbs into classes recognizing distinct epitopes on the SRBD as well as distinct conformational states of the S trimer. Potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two mouse models of SARS-CoV-2 infection, passive transfer of either COV2-2196 or COV2-2130 alone or a combination of both mAbs protected mice from weight loss and reduced viral burden and inflammation in the lung. In addition, passive transfer of each of two of the most potently ACE2 blocking mAbs (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutics

Akaike information criteria with small sample bias adjustment (AICc); number of parameters (K), ΔAICc, Akaike weights (<i>w</i>) for candidate models (<i>i</i>) relating prevalence of detecting <i>Trueperella pyogenes</i> on the mucosal surfaces of deer to the occurrence of cranial abscess disease at 29 sites across Georgia, USA in 2011–2012.

<p>^a Models correspond to prevalence of <i>T</i>. <i>pyogenes</i> on: O = overall (i.e., detection at any of the three dermal linings sampled), H = Forehead, N = Nasal, T = Tongue.</p><p>^bNumber of estimating parameters in approximating model.</p><p>^c Models with ΔAICc ≤ 2 were considered good candidates for explaining patterns in field data, models with ΔAICc 2–7 had little support, and models with ΔAICc > 10 had relatively no support.</p><p>^dAkaike weight.</p><p>The detection of <i>T</i>. <i>pyogenes</i> on any mucosal surface (overall detection) has the lowest AICc score.</p

Epethelial Presence of <i>Trueperella pyogenes</i> Predicts Site-Level Presence of Cranial Abscess Disease in White-Tailed Deer (<i>Odocoileus virginianus</i>)

<div><p>Cranial/intracranial abscess disease is an emerging source of significant mortality for male white-tailed deer (<i>Odocoileus virginianus</i>). Most cases of cranial/intracranial abscess disease are associated with infection by the opportunistic pathogen <i>Trueperella pyogenes</i> although the relationship between the prevalence of the bacteria and occurrence of disease is speculative. We examined 5,612 hunter-harvested deer from 29 sites across all physiographic provinces in Georgia for evidence of cranial abscess disease and sampled the forehead, lingual, and nasal surfaces from 692 deer. We used polymerase chain reaction (PCR) to determine presence of <i>T</i>. <i>pyogenes</i> from these samples. We found <i>T</i>. <i>pyogenes</i> prevalence at a site was a predictor for the occurrence of cranial abscess disease. Prevalence of <i>T</i>. <i>pyogenes</i> did not differ between samples from the nose or tongue although prevalence along the forehead was greater for males than females (p = 0.04), particularly at sites with high occurrence of this disease. Socio-sexual behaviors, bacterial prevalence, or physiological characteristics may predispose male deer to intracranial/cranial abscess disease. Determination of factors that affect <i>T</i>. <i>pyogenes</i> prevalence among sites may help explain the occurrence of this disease among populations.</p></div

Location of 29 sites and the number of hunter-harvested adult (≥1.5 years old) male white-tailed deer testing positive for cranial abscess disease and the number examined for the presence of the cranial abscess disease in Georgia, USA during Fall 2011 and 2012.

<p>Location of 29 sites and the number of hunter-harvested adult (≥1.5 years old) male white-tailed deer testing positive for cranial abscess disease and the number examined for the presence of the cranial abscess disease in Georgia, USA during Fall 2011 and 2012.</p

Pearson correlations (r) for fixed effect variables used in our modeling exercises.

<p>First, we examined if the detection of <i>Trueperella pyogenes</i> on one mucosal layer was associated with higher chance of detecting it at other mucosal layers. White-tailed deer were sampled along the forehead, nose, and tongue for presence of <i>T</i>. <i>pyogenes</i>. The prevalence of <i>T</i>. <i>pyogenes</i> on these mucosal layers across deer sampled at each site was used as predictor variables in subsequent modeling exercises to determine if associations with increased risk of cranial abscess disease at the site level. We then ensured no collinearity between the age and gender. No variables were significantly correlated enough to be excluded from being in the same model (cutoff of r = ± 0.70).</p