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Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures. Diamond and colleagues generate a K18-hACE2 model of SARS-CoV-2 infection that shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.

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.

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.

Cranial/intracranial abscess disease is an emerging source of significant mortality for male white-tailed deer (Odocoileus virginianus). Most cases of cranial/intracranial abscess disease are associated with infection by the opportunistic pathogen Trueperella pyogenes 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 T. pyogenes from these samples. We found T. pyogenes prevalence at a site was a predictor for the occurrence of cranial abscess disease. Prevalence of T. pyogenes 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 T. pyogenes prevalence among sites may help explain the occurrence of this disease among populations.

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health 1 and the medical countermeasures available so far are limited 2 , 3 . Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-2 4 . Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein 5 , and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (S RBD ) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the S RBD , as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the S RBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents. An analysis identifies human monoclonal antibodies that potently neutralize wild-type SARS-CoV-2 and protect animals from disease, including two that synergize in a cocktail, suggesting that these could be candidates for use as therapeutic agents for the treatment of COVID-19 in humans.

BACKGROUND: The persistence of influenza A (IA) virus in aquatic habitats has been demonstrated to be a determinant for virus transmission dynamics in wild duck populations. In this study, we investigated virus strain-related variation in persistence in water for nine wild duck isolated IA viruses of three subtypes (H3N8, H4N6, and H8N4). RESULTS: We experimentally estimated the loss of infectivity over time in three different types of water: distilled, filtered surface water, and intact surface water. All viruses persisted longest in distilled water followed by filtered surface water with markedly reduced durations of persistence observed in the intact surface water. Strain-related variations were observed in distilled and filtered surface water but limited variation was observed in the intact surface water. CONCLUSIONS: Our findings suggest that the role of surface water for long-term (between years) maintenance of AI viruses in the environment may be limited, and suggest that the physico-chemical characteristics of water, as well as microorganisms, may be of strong importance. Results also indicate that the extent of strain-related variation observed in distilled water may overestimate persistence abilities for IA viruses in the wild and supports the need to develop experiments that account for these effects to assess subtype, genotype, as well as spatial and temporal variation in the persistence of IA viruses in aquatic habitats.

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.

New studies of chronic obstructive pulmonary disease (COPD) are revealing the key role of airway epithelial cells and innate immune cells in the initiation, exacerbation, and progression of airway disease. An emerging scheme focuses on expansion of airway progenitor epithelial cells that feed forward for a type 2 immune response and consequent IL-13-driven mucus production that is linked to the morbidity and mortality of COPD. Analysis of human airway progenitor epithelial cells and airway tissue shows that IL-13 signaling to MUC5AC mucin gene expression relies on specific activation of mitogen-activated protein kinase 13, providing a druggable target for attenuating mucus production in the setting of viral infection and other inhaled stimuli of airway inflammation. Moreover, structure-based drug design is delivering highly potent, selective, and nontoxic small-molecule kinase inhibitors of mitogen-activated protein kinase 13 that offer a therapeutic strategy to downregulate excess mucus production to a physiological level and thereby achieve a precision medicine solution to the major health care problem of COPD and related airway diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Five of 16 (31%) rufous-capped warblers (Basileuterus rufifrons) and 2 of 5 (40%) ovenbirds (Seiurus aurocapilla) sampled from Costa Rica were positive for a novel species of Isospora. Oocysts have a thin, smooth, double-layered, colorless wall and measure 22.3 μm ± 1.6 μm × 24.3 μm ± 1.5 μm (19–25 μm × 21–28 μm) with an average length-width (L/W) ratio of 1.0 (1–1.3). Oocyst residuum and micropyle are absent, but 0–4 spherical to cigar-shaped polar granules (1–2.5 μm) are present. Sporocysts are ovoid and measure 11.8 μm ± 0.9 μm × 16 μm ± 1.7 μm (10–14 μm × 12–19 μm) with an average L/W ratio of 1.6 (1.0–1.9). A knob-like Stieda body continuous with the sporocyst wall and a trapezoidal compartmentalized substieda body are present. Each sporocyst contained 4 sporozoites and a diffuse sporocyst residuum consisting of many variable-sized granules, some as large as 2 μm. This is the second description of an Isospora species in New World warblers (Passeriformes: Parulidae) and the first report of Isospora from both the rufous-capped warbler and ovenbird.