Middle East respiratory syndrome coronavirus (MERS-CoV) targets the epithelial cells of the respiratory tract both in humans and in its natural host, the dromedary camel. Virion attachment to host cells is mediated by 20-nm-long homotrimers of spike envelope protein S. The N-terminal subunit of each S protomer, called S1, folds into four distinct domains designated S1 through S1 Binding of MERS-CoV to the cell surface entry receptor dipeptidyl peptidase 4 (DPP4) occurs via S1 We now demonstrate that in addition to DPP4, MERS-CoV binds to sialic acid (Sia). Initially demonstrated by hemagglutination assay with human erythrocytes and intact virus, MERS-CoV Sia-binding activity was assigned to S subdomain S1 When multivalently displayed on nanoparticles, S1 or S1 bound to human erythrocytes and to human mucin in a strictly Sia-dependent fashion. Glycan array analysis revealed a preference for α2,3-linked Sias over α2,6-linked Sias, which correlates with the differential distribution of α2,3-linked Sias and the predominant sites of MERS-CoV replication in the upper and lower respiratory tracts of camels and humans, respectively. Binding is hampered by Sia modifications such as 5--glycolylation and (7,)9--acetylation. Depletion of cell surface Sia by neuraminidase treatment inhibited MERS-CoV entry of Calu-3 human airway cells, thus providing direct evidence that virus-Sia interactions may aid in virion attachment. The combined observations lead us to propose that high-specificity, low-affinity attachment of MERS-CoV to sialoglycans during the preattachment or early attachment phase may form another determinant governing the host range and tissue tropism of this zoonotic pathogen.

Middle East respiratory syndrome (MERS) cases continue to be reported, predominantly in Saudi Arabia and occasionally other countries. Although dromedaries are the main reservoir, other animal species might be susceptible to MERS coronavirus (MERS-CoV) infection and potentially serve as reservoirs. To determine whether other animals are potential reservoirs, we inoculated MERS-CoV into llamas, pigs, sheep, and horses and collected nasal and rectal swab samples at various times. The presence of MERS-CoV in the nose of pigs and llamas was confirmed by PCR, titration of infectious virus, immunohistochemistry, and in situ hybridization; seroconversion was detected in animals of both species. Conversely, in sheep and horses, virus-specific antibodies did not develop and no evidence of viral replication in the upper respiratory tract was found. These results prove the susceptibility of llamas and pigs to MERS-CoV infection. Thus, the possibility of MERS-CoV circulation in animals other than dromedaries, such as llamas and pigs, is not negligible.

Middle East respiratory syndrome coronavirus (MERS-CoV) is not efficiently transmitted between humans, but it is highly prevalent in dromedary camels. Here we report that the MERS-CoV receptor-dipeptidyl peptidase 4 (DPP4)-is expressed in the upper respiratory tract epithelium of camels but not in that of humans. Lack of DPP4 expression may be the primary cause of limited MERS-CoV replication in the human upper respiratory tract and hence restrict transmission. Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel coronavirus that causes pneumonia in humans, which may lead to acute respiratory distress syndrome (1). Currently, more than 1,500 confirmed cases have been reported, with a relatively high case fatality rate. Although most MERS outbreaks have been reported in the Middle Eastern countries, travel-related cases may seed outbreaks in other regions, such as in South Korea (2). In principle, they can be controlled through implementation of early viral diagnostics, strict hygiene measures, and isolation of patients. However, there is still a lack of understanding of how this virus is transmitted, both between humans and from camels to humans.Dromedary camels are currently considered the only zoonotic source of MERS-CoV. This is largely based on the fact that closely related viruses have been isolated only from this species thus far (3, 4). Although studies in the Middle East and several northeastern African countries revealed a high percentage of serological positivity among dromedary camels (3, 5-8), there seems to be limited MERS-CoV transmission from camels to humans. Recent studies have shown that only 2 to 3% of persons in Saudi Arabia and Qatar that come into close contact with dromedary camels have neutralizing antibodies to MERS-CoV (5, 9). Additionally, most of the notified MERS patients to date did not report any contact with camels or other livestock animals, consistent with the fact that most outbreaks took place in hospitals (10, 11). On the other hand, studies in hospital and household settings also reported a low percentage of confirmed MERS cases among patient contacts (10, 11). As a result, over a 3-year period, the number of MERS cases is relatively low, providing evidence that MERS-CoV transmission to humans and between humans is relatively inefficient.One factor considered to be critical for the transmission of MERS-CoV is the ability of the virus to replicate in the upper respiratory tract. Differences in viral shedding in dromedary camels and humans have been observed. Relatively high levels of infectious virus can be detected in nasal swabs of dromedaries infected with MERS-CoV but not in MERS patients (12, 13). We hypothesized that a critical determinant of MERS-CoV replication in the respiratory tracts of different hosts is the differential expression of the viral receptor. Dipeptidyl peptidase 4 (DPP4), a serine exopeptidase involved in various biological functions (14), has been shown to act as the functional MERS-CoV receptor (15). Although there is ample evidence th...

We provide evidence that DPP4 is upregulated in the lungs of smokers and COPD patients, which could partially explain why these individuals are more susceptible to MERS-CoV infection. These data also highlight a possible role of DPP4 in COPD pathogenesis.