Kallikrein 13: a new player in coronaviral infections

Abstract

35Human coronavirus HKU1 (HCoV-HKU1) is associated with respiratory disease and is 36 prevalent worldwide, but in vitro model for virus replication is lacking. Interaction between the 37 coronaviral spike (S) protein and its receptor is the major determinant of virus tissue and host 38 specificity, but virus entry is a complex process requiring a concerted action of multiple cellular 39 elements. Here, we show that KLK13 is required for the infection of the human respiratory 40 epithelium and is sufficient to mediate the entry of HCoV-HKU1 to non-permissive RD cells. 41 We also demonstrated HCoV-HKU1 S protein cleavage by KLK13 in the S1/S2 region, proving 42 that KLK13 is the priming enzyme for this virus. Summarizing, we show for the first time that 43 protease distribution and specificity predetermines the tissue and cell specificity of the virus 44 and may also regulate interspecies transmission. It is also of importance that presented data may 45 be relevant for the emerging coronaviruses, including SARS-CoV-2 and may help to understand 46 the differences in their zoonotic potential. : bioRxiv preprint 48Coronaviruses are the largest group within the order Nidovirales. Mainly, they cause 49 respiratory and enteric diseases in humans and animals, but some can cause more serious 50 conditions such as hepatitis, peritonitis, or neurological disease. Seven coronaviruses infect 51 humans, four of which (human coronavirus [HCoV]-229E, HCoV-NL63, HCoV-OC43, and 52 HCoV-HKU1) cause relatively mild upper and lower respiratory tract disease and two (SARS-53 CoV and MERS-CoV) are associated with severe, life-threatening respiratory infections and 54 multiorgan failure (1-6). Furthermore, in December 2019 a novel coronavirus SARS-CoV-2 55 emerged in Hubei province, China, causing pneumonia. To date, almost 90,000 cases were 56 identified and 3,000 patients died worldwide. 57 Coronaviral infection is initiated by interaction between the trimeric spike (S) protein 58 and its receptor, which is expressed on the surface of the susceptible cell. A number of adhesion 59 and entry receptors have been described for coronaviruses. For example, HCoV-229E (similar 60 to many other alphacoronaviruses) utilizes aminopeptidase N (APN) as the primary entry port 61 (7). Surprisingly, its cousin HCoV-NL63 shares receptor specificity with the evolutionarily 62 distant SARS-CoV and SARS-CoV-2: all hijack angiotensin-converting enzyme 2 (ACE2) (8-63 11). HCoV-NL63 was also shown to use heparan sulfate as a primary attachment site (12-14). 64 A very different receptor is recognized by MERS-CoV, which binds to dipeptidyl-peptidase 4 65 (DPP4) (9, 15, 16). Another betacoronavirus, HCoV-OC43, binds to N-acetyl-9-O-66 acetylneuraminic acid (17, 18). HCoV-HKU1 remains the great unknown because its cellular 67 receptor has not been identified and all efforts to culture the virus in vitro have failed.68 HCoV-HKU1 was identified in Hong Kong in 2004. The virus was present in a sample 69 obtained from an elderly patient with severe pneumonia (...

Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility

“…Plasmin also cleaves the S proteins of SARS-CoV in vitro (37). In addition, HCoV-HKU1 S proteins are cleaved by kallikrein in the S1/S2 region and mediate the entry of HCoV-HKU1 to nonpermissive rhabdomyosarcoma cells (54). The clinical relevance of non-furin cleavage remains unknown due to the paucity of in vivo evidence for the role of plasmin cleavage of SARS-CoV.…”

Replication of SARS-CoV-2 in human respiratory epithelium

“…While in the first one they enter via pH-dependent endocytic pathway, in 77 the latter one they utilize surface serine proteases as TMPRSS2 or kallikreins for activation and 78 the fusion occurs on the cell surface. This may have grave consequences not only for the basic 79 science, but also the antiviral drug development 12,13,14,20 . 80 Here we verified whether HAE cultures may be used to study the SARS-CoV-2 infection 81 and identified the cellular targets in the tissue.…”

A Review: Does Complement or the Contact System Have a Role in Protection or Pathogenesis of COVID-19?

“…Although the literature surrounding the contact system and coronavirus is limited, there has been recent work about the roles of kallikrein and angiotensin-converting enzyme (ACE). In a preliminary study by Milewska et al, researchers studied the role of kallikrein 13 (KLK13) in HCoV-HKU1, a coronavirus discovered in Hong Kong in 2004 [14]. Human airway epithelial (HAE) cell cultures were incubated with HCoV.…”

“…Based on mRNA expression, human tissue kallikreins (KLK) KLK1, KLK5, KLK6, KLK9, KLK12 and KLK14 were significantly expressed in the infected cells. In particular, HCoV-HKU1 infection was dependent on KLK13 activity, and HCoV-HKU1 did not replicate in HAE cells deficient in KLK13 [14]. Perhaps KLK13 inhibitors could serve as a novel therapy to prevent or treat coronavirus infections.…”

“…The B1 receptor on endothelial cells is up-regulated by inflammatory cytokines, which is unlike the B2 receptor that is constituently expressed and is the receptor for bradykinin. Without ACE2 to inactivate des-Arg bradykinin bound to the B1 receptor, the lung is subject to angioedema [14].…”