MERS coronavirus induces apoptosis in kidney and lung by upregulating Smad7 and FGF2

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes sporadic zoonotic disease and healthcare-associated outbreaks in human. MERS is often complicated by acute respiratory distress syndrome (ARDS) and multi-organ failure(1,2). The high incidence of renal failure in MERS is a unique clinical feature not often found in other human coronavirus infections(3,4). Whether MERS-CoV infects the kidney and how it triggers renal failure are not understood(5,6). Here, we demonstrated renal infection and apoptotic induction by MERS-CoV in human ex vivo organ culture and a nonhuman primate model. High-throughput analysis revealed that the cellular genes most significantly perturbed by MERS-CoV have previously been implicated in renal diseases. Furthermore, MERS-CoV induced apoptosis through upregulation of Smad7 and fibroblast growth factor 2 (FGF2) expression in both kidney and lung cells. Conversely, knockdown of Smad7 effectively inhibited MERS-CoV replication and protected cells from virus-induced cytopathic effects. We further demonstrated that hyperexpression of Smad7 or FGF2 induced a strong apoptotic response in kidney cells. Common marmosets infected by MERS-CoV developed ARDS and disseminated infection in kidneys and other organs. Smad7 and FGF2 expression were elevated in the lungs and kidneys of the infected animals. Our results provide insights into the pathogenesis of MERS-CoV and host targets for treatment.

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

“…Prior to December 2019, 6 CoVs were known to infect human, including 2 αCoV (HCoV-229E and HKU-NL63) and 4 βCoV (HCoV-OC43 [lineage A], HCoV-HKU1 [lineage A], SARS-CoV [lineage B] and MERS-CoV [lineage C]). The βCoV lineage A HCoV-OC43 and HCoV-HKU1 usually cause self-limiting upper respiratory infections in immunocompetent hosts and occasionally lower respiratory tract infections in immunocompromised hosts and elderly [4].…”

“…The βCoV lineage A HCoV-OC43 and HCoV-HKU1 usually cause self-limiting upper respiratory infections in immunocompetent hosts and occasionally lower respiratory tract infections in immunocompromised hosts and elderly [4]. In contrast, SARS-CoV (lineage B βCoV) and MERS-CoV (lineage C βCoV) may cause severe lower respiratory tract infection with acute respiratory distress syndrome and extrapulmonary manifestations, such as diarrhea, lymphopenia, deranged liver and renal function tests, and multiorgan dysfunction syndrome, among both immunocompetent and immunocompromised hosts with mortality rates of ∼10% and ∼35%, respectively [5,6]. On 31 December 2019, the World Health Organization (WHO) was informed of cases of pneumonia of unknown cause in Wuhan City, Hubei Province, China [7].…”

Middle East respiratory syndrome

“…47 Further, ex vivo human kidney cultures were shown to support productive MERS-CoV infection. 48 However, it is not known whether infection of this organ contributes to worse outcomes compared with infections confined to the respiratory tract. Viral RNA, but not infectious MERS-CoV, was detected in the blood for at least 2 weeks after diagnosis.…”

Emerging respiratory infections: The infectious disease pathology of SARS, MERS, pandemic influenza, and Legionella

“…33 Studies in kidney explants demonstrated infection of multiple cell types including renal tubular cells, vascular endothelial cells, and podocytes. 34 Experimental infection of small intestine explants with MERS-CoV demonstrated infection limited to the surface enterocytes and formation of syncytial cells. In keeping with these observations, infected patients have been found to shed virus in their urine and stool.…”