NLRP1 restricts porcine deltacoronavirus infection via IL-11 inhibiting the phosphorylation of the ERK signaling pathway.

Continuously emerging highly pathogenic coronaviruses remain a major threat to human and animal health. Porcine deltacoronavirus (PDCoV) is a newly emerging enterotropic swine coronavirus that causes large-scale outbreaks of severe diarrhea disease in piglets. Unlike other porcine coronaviruses, PDCoV has a wide range of species tissue tropism, including primary human cells, which poses a significant risk of cross-species transmission. Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) has a key role in linking host innate immunity to microbes and the regulation of inflammatory pathways. We now report a role for NLRP1 in the control of PDCoV infection. Overexpression of NLRP1 remarkably suppressed PDCoV infection, whereas knockout of NLRP1 led to a significant increase in PDCoV replication. A mechanistic study revealed that NLRP1 suppressed PDCoV replication in cells by upregulating IL-11 expression, which in turn inhibited the phosphorylation of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor U0126 effectively hindered PDCoV replication in pigs. Together, our results demonstrated that NLRP1 exerted an anti-PDCoV effect by IL-11-mediated inhibition of the phosphorylation of the ERK signaling pathway, providing a novel antiviral signal axis of NLRP1-IL-11-ERK. This study expands our understanding of the regulatory network of NLRP1 in the host defense against virus infection and provides a new insight into the treatment of coronaviruses and the development of corresponding drugs.IMPORTANCECoronavirus, which mainly infects gastrointestinal and respiratory epithelial cells in vivo, poses a huge threat to both humans and animals. Although porcine deltacoronavirus (PDCoV) is known to primarily cause fatal diarrhea in piglets, reports detected in plasma samples from Haitian children emphasize the potential risk of animal-to-human spillover. Finding effective therapeutics against coronaviruses is crucial for controlling viral infection. Nucleotide-binding oligomerization-like receptor (NLR) family pyrin domain-containing 1 (NLRP1), a key regulatory factor in the innate immune system, is highly expressed in epithelial cells and associated with the pathogenesis of viruses. We demonstrate here that NLRP1 inhibits the infection of the intestinal coronavirus PDCoV through IL-11-mediated phosphorylation inhibition of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor can control the infection of PDCoV in pigs. Our study emphasizes the importance of NLRP1 as an immune regulatory factor and may open up new avenues for the treatment of coronavirus infection.

First isolation and whole genome characterization of porcine deltacoronavirus from pigs in Peru.

Porcine deltacoronavirus is a newly emergent enteric pathogen affecting swine farms worldwide. It has been detected in several countries in Europe, Asia and North America; yet, it has not been reported in South America. In November 2019, an enteric disease outbreak in a pig farm located in San Martin, Peru, was reported along with submission of three intestinal samples from pigs who succumbed to the disease. Samples were processed for molecular detection by qRT-PCR, viral isolation and further sequencing analysis. A taqman-based RT-PCR was performed to differentiate among the most relevant swine enteric coronaviruses described to date. All samples were positive to porcine deltacoronavirus with a cycle threshold (Ct) value between 9 and 14, revealing a high viral load, while testing negative to porcine epidemic diarrhea and transmissible gastroenteritis viruses. Following detection, viral isolation was performed using PK-15 and Vero cell lines. After 5 days of inoculation, no cytopathic effect was observed. A second blind passage allowed the observation of cytopathic effect on PK-15 cells, while it remained absent in Vero cells. A fluorescence test using an anti-N monoclonal antibody confirmed viral replication. One sample was processed for whole genome sequencing (WGS). In short, raw reads were imported into CLC genomics and assembled de novo. Out of 479k reads generated from the sample, 436k assembled into a 25,501 bp contig which was 99.5% identical to a reference porcine deltacoronavirus strain from the USA within the North American phylogroup. Yet, there are relevant differences at the nucleotide and amino acid levels compared with previously described porcine deltacoronavirus strains. Altogether, our findings represent the first report of porcine deltacoronavirus in South America, which provides information of its evolutionary origin. Thus, this study offers new insights into the molecular epidemiology of porcine deltacoronavirus infections in the swine industry.

Independent infections of porcine deltacoronavirus among Haitian children.

Coronaviruses have caused three major epidemics since 2003, including the ongoing SARS-CoV-2 pandemic. In each case, the emergence of coronavirus in our species has been associated with zoonotic transmissions from animal reservoirs1,2, underscoring how prone such pathogens are to spill over and adapt to new species. Among the four recognized genera of the family Coronaviridae, human infections reported so far have been limited to alphacoronaviruses and betacoronaviruses3-5. Here we identify porcine deltacoronavirus strains in plasma samples of three Haitian children with acute undifferentiated febrile illness. Genomic and evolutionary analyses reveal that human infections were the result of at least two independent zoonoses of distinct viral lineages that acquired the same mutational signature in the genes encoding Nsp15 and the spike glycoprotein. In particular, structural analysis predicts that one of the changes in the spike S1 subunit, which contains the receptor-binding domain, may affect the flexibility of the protein and its binding to the host cell receptor. Our findings highlight the potential for evolutionary change and adaptation leading to human infections by coronaviruses outside of the previously recognized human-associated coronavirus groups, particularly in settings where there may be close human-animal contact.

Epidemiological Update: Coronavirus disease (COVID-19) (27 September 2021)

As of the end of the epidemiological week 37 (end date 18 September 2021), 228,068,334 confirmed cumulative cases of COVID-19 have been reported globally, including 4,685,658 deaths, for which the Region of the Americas contributed 38.6% of cases and 46.4% of deaths. The North America subregion accounted for the highest proportions of monthly cases (69%) and deaths (51%) in the month of August for the Region of the Americas. Although an overall decreasing trend in deaths is observed at the Regional level between July and August 2021, deaths have increased in all subregions except for South America, where a decline of 53% in deaths is noted. The North America and Caribbean subregions experienced the highest percent increases both in cases (172% and 54%, respectively) and deaths (205% and 61%, respectively) compared to those reported in July 2021.

Hasta el final de la semana epidemiológica 37 (terminando en el día 18 de septiembre 2021), fueron notificados 228.068.334 casos acumulados confirmados de COVID-19 a nivel global, incluyendo 4.685.658 defunciones. El 38,6% de los casos y 46,4% de las defunciones globales fueron aportadas por la región de las Américas. La subregión de América del Norte presentó las mayores proporciones de casos mensuales (69%) y de defunciones (51%) en el mes de agosto para la Región de las Américas. Aunque se observa una tendencia a la disminución de las defunciones a nivel regional entre julio y agosto de 2021, las defunciones han aumentado en todas las subregiones, excepto en América del Sur, donde se observa una disminución del 53% de las defunciones. Las subregiones de América del Norte y el Caribe tuvieron los mayores aumentos porcentuales tanto de casos (172% y 54%, respectivamente) como de defunciones (205% y 61%, respectivamente) en comparación con los notificados en julio de 2021.

Epidemiological Update: Coronavirus disease (COVID-19) (21 August 2021)

As of 20 August 2021, 210,112,064 confirmed cumulative cases of COVID-19 have been reported globally, including 4,403,765 deaths, for which the Region of the Americas contributed 39% of cases and 47% of deaths. Although the South America subregion continued to account for the highest proportions of monthly cases (54.6%) and deaths (79.8%) in the month of July for the Region of the Americas, a decreasing trend has been observed for the first time since February 2021. Meanwhile, the North America subregion has experienced an increase of 233% in cases compared to the previous month. As of 20 August 2021, Antigua and Barbuda, Argentina, Aruba, Brazil, Canada, the Cayman Islands, Chile, Costa Rica, Curacao, French Guiana, Guadeloupe, Guatemala, Martinique, Mexico, Panama, Puerto Rico, Sint Maarten, Suriname, the United States of America, and Uruguay have detected all four variants of concern (VOC). Among indigenous populations in 18 countries of the Americas, 604,264 cases were reported, including 15,027 deaths. A total of 24 countries and territories have reported 7,030 cumulative confirmed cases of multisystem inflammatory syndrome in children and adolescents (MIS-C) temporally related to COVID-19, including 138 deaths. Regarding health workers, 39 countries and territories have reported 1,792,212 cases, including 10,302 deaths.

Epidemiological Update: Increase of the Delta variant and its potential impact in the Region of the Americas (8 August 2021)

Since the initial identification of SARS-CoV-2, as of 5 August 2021, more than 2.6 million complete genomic sequences have been shared worldwide, providing visibility and public access to this information. The ability to monitor viral evolution, almost in real time, has a direct impact on the public health response to the COVID-19 pandemic, as it allows the identification of changes in epidemiological patterns, changes in virulence, or even a decrease in the preventive efficacy of vaccines, among other contributions. Globally, several countries with an increase in cases and hospitalizations with the emergence of Variant of Concern (VOC) Delta can be observed (Figure 1), including Member States in the Americas with high vaccination coverage. With the VOC Gamma as the predominant variant in several countries and territories of the Americas, and the emergence of the identification of VOC Delta in these same countries and territories, in addition to other variants of interest (VOI) (Figure 2), such as Lambda, for example, exhorts the necessity to point out to the Member States of the region the importance of the preparatory process for the expansion of care capacity in the face of a potential increase in cases, hospitalizations, and deaths.

Atualização epidemiológica: Incremento de variante Delta e seu potencial impacto na região das Américas (8 de agosto de 2021)

Desde a identificação inicial do SARS-CoV-2, até 05 de agosto de 2021, vem sendo compartilhado, a nível mundial, mais de 2,6 milhões de sequências genômicas completas, dando visibilidade e acesso público a estas informações. A capacidade de monitorar a evolução viral, quase em tempo real, tem impacto direto na resposta de saúde pública frente a pandemia de COVID-19, pois permite identificar mudanças nos padrões epidemiológicos, alteração a virulência, ou ainda, a diminuição da eficácia preventiva das vacinas, entre outras contribuições. Em nível global, se observam vários países com aumento de casos e de hospitalizações, com a emergência da Variante de preocupação (VOC, pelas suas siglas em inglês) Delta (Figura 1), incluindo Estados Membros das Américas com alta cobertura vacinal. A constante manutenção da VOC Gamma como variante predominante em vários países e territórios das Américas, e a emergência da identificação da VOC Delta nestes mesmos países e territórios, além de outras VOI (Figura 2), como a Lambda por exemplo, nos traz a necessidade de sinalizar aos Estados Membros da região a importância de processo preparatório da ampliação da capacidade de atenção frente a potencial incremento de casos, hospitalizações e óbitos.