†Present address: Center for Translational Cancer Research (CTCR), Institute of Biosciences and Technology (IBT), Texas A&M Health Science Center, Houston, TX, USA.
Nipah virus (NiV) is an emerging paramyxovirus that can cause lethal respiratory illness in humans. No vaccine/therapeutic is currently licensed for humans. Human-to-human transmission was previously reported during outbreaks and NiV could be isolated from respiratory secretions, but the proportion of cases in Malaysia exhibiting respiratory symptoms was significantly lower than that in Bangladesh. Previously, we showed that primary human basal respiratory epithelial cells are susceptible to both NiV-Malaysia (M) and -Bangladesh (B) strains causing robust pro-inflammatory responses. However, the cells of the human respiratory epithelium that NiV targets are unknown and their role in NiV transmission and NiV-related lung pathogenesis is still poorly understood. Here, we characterized NiV infection of the human respiratory epithelium using a model of the human tracheal/bronchial (B-ALI) and small airway (S-ALI) epithelium cultured at an air–liquid interface. We show that NiV-M and NiV-B infect ciliated and secretory cells in B/S-ALI, and that infection of S-ALI, but not B-ALI, results in disruption of the epithelium integrity and host responses recruiting human immune cells. Interestingly, NiV-B replicated more efficiently in B-ALI than did NiV-M. These results suggest that the human tracheal/bronchial epithelium is favourable to NiV replication and shedding, while inducing a limited host response. Our data suggest that the small airways epithelium is prone to inflammation and lesions as well as constituting a point of virus entry into the pulmonary vasculature. The use of relevant models of the human respiratory tract, such as B/S-ALI, is critical for understanding NiV-related lung pathogenesis and identifying the underlying mechanisms allowing human-to-human transmission.
BaggioliniM.,
ImbodenP.,
DetmersP.1992; Neutrophil activation and the effects of interleukin-8/neutrophil-activating peptide 1 (IL-8/NAP-1). Cytokines 4:1–17[PubMed][CrossRef]
BaselerL.,
de WitE.,
ScottD. P.,
MunsterV. J.,
FeldmannH.2015; Syrian hamsters (Mesocricetus auratus) oronasally inoculated with a Nipah virus isolate from Bangladesh or Malaysia develop similar respiratory tract lesions. Vet Pathol 52:38–45 [View Article][PubMed]
ChongH. T.,
KunjapanS. R.,
ThayaparanT.,
TongJ. M. G.,
PetharunamV.,
JusohM. R.,
TanC. T.2002; Nipah encephalitis outbreak in Malaysia, clinical features in patients from Seremban. Can J Neurol Sci 29:83–87 [View Article][PubMed]
ChuaK. B.,
LamS. K.,
GohK. J.,
HooiP. S.,
KsiazekT. G.,
KamarulzamanA.,
OlsonJ.,
TanC. T.2001; The presence of Nipah virus in respiratory secretions and urine of patients during an outbreak of Nipah virus encephalitis in Malaysia. J Infect 42:40–43 [View Article][PubMed]
ClahsenT.,
SchaperF.2008; Interleukin-6 acts in the fashion of a classical chemokine on monocytic cells by inducing integrin activation, cell adhesion, actin polymerization, chemotaxis, and transmigration. J Leukoc Biol 84:1521–1529 [View Article][PubMed]
DeBuysscherB. L.,
de WitE.,
MunsterV. J.,
ScottD.,
FeldmannH.,
PrescottJ.2013; Comparison of the pathogenicity of Nipah virus isolates from Bangladesh and Malaysia in the Syrian hamster. PLoS Negl Trop Dis 7:e2024 [View Article][PubMed]
GerlachR. L.,
CampJ. V.,
ChuY. K.,
JonssonC. B.2013; Early host responses of seasonal and pandemic influenza A viruses in primary well-differentiated human lung epithelial cells. PLoS One 8:e78912 [View Article][PubMed]
GohK. J.,
TanC. T.,
ChewN. K.,
TanP. S.,
KamarulzamanA.,
SarjiS. A.,
WongK. T.,
AbdullahB. J.,
ChuaK. B.,
LamS. K.2000; Clinical features of Nipah virus encephalitis among pig farmers in Malaysia. N Engl J Med 342:1229–1235 [View Article][PubMed]
GurleyE. S.,
MontgomeryJ. M.,
HossainM. J.,
BellM.,
AzadA. K.,
IslamM. R.,
MollaM. A.,
CarrollD. S.,
KsiazekT. G.,
other authors.
2007; Person-to-person transmission of Nipah virus in a Bangladeshi community. Emerg Infect Dis 13:1031–1037 [View Article][PubMed]
HaritA. K.,
IchhpujaniR. L.,
GuptaS.,
GillK. S.,
LalS.,
GangulyN. K.,
AgarwalS. P.2006; Nipah/Hendra virus outbreak in Siliguri, West Bengal, India in 2001. J Med Res 123:553–560[PubMed]
HooperP.,
ZakiS.,
DanielsP.,
MiddletonD.2001; Comparative pathology of the diseases caused by Hendra and Nipah viruses. Microbes Infect 3:315–322 [View Article][PubMed]
LamE.,
RamkeM.,
WarneckeG.,
SchrepferS.,
KopfnagelV.,
DobnerT.,
HeimA.2015; Effective apical infection of differentiated human bronchial epithelial cells and induction of proinflammatory chemokines by the highly pneumotropic human adenovirus type 14p1. PLoS One 10:e0131201 [View Article][PubMed]
LoM. K.,
MillerD.,
AljofanM.,
MungallB. A.,
RollinP. E.,
BelliniW. J.,
RotaP. A.2010; Characterization of the antiviral and inflammatory responses against Nipah virus in endothelial cells and neurons. Virology 404:78–88 [View Article][PubMed]
LusterA. D.,
LederP.1993; IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo. J Exp Med 178:1057–1065 [View Article][PubMed]
MatrosovichM. N.,
MatrosovichT. Y.,
GrayT.,
RobertsN. A.,
KlenkH. D.2004; Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc Natl Acad Sci U S A 101:4620–4624 [View Article][PubMed]
MercerR. R.,
RussellM. L.,
RoggliV. L.,
CrapoJ. D.1994; Cell number and distribution in human and rat airways. Am J Respir Cell Mol Biol 10:613–624 [View Article][PubMed]
MitchellH.,
LevinD.,
ForrestS.,
BeaucheminC. A.,
TipperJ.,
KnightJ.,
DonartN.,
LaytonR. C.,
PylesJ.,
other authors.
2011; Higher level of replication efficiency of 2009 (H1N1) pandemic influenza virus than those of seasonal and avian strains: kinetics from epithelial cell culture and computational modeling. J Virol 85:1125–1135 [View Article][PubMed]
MountsA. W.,
KaurH.,
ParasharU. D.,
KsiazekT. G.,
CannonD.,
ArokiasamyJ. T.,
AndersonL. J.,
LyeM. S.,
Nipah Virus Nosocomial Study Group.
2001; A cohort study of health care workers to assess nosocomial transmissibility of Nipah virus, Malaysia, 1999. J Infect Dis 183:810–813 [View Article][PubMed]
PatonN. I.,
LeoY. S.,
ZakiS. R.,
AuchusA. P.,
LeeK. E.,
LingA. E.,
ChewS. K.,
AngB.,
RollinP. E.,
other authors.
1999; Outbreak of Nipah-virus infection among abattoir workers in Singapore. Lancet 354:1253–1256 [View Article][PubMed]
RockJ. R.,
RandellS. H.,
HoganB. L.2010; Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis Model Mech 3:545–556 [View Article][PubMed]
RockxB.,
SheahanT.,
DonaldsonE.,
HarkemaJ.,
SimsA.,
HeiseM.,
PicklesR.,
CameronM.,
KelvinD.,
BaricR.2007; Synthetic reconstruction of zoonotic and early human severe acute respiratory syndrome coronavirus isolates that produce fatal disease in aged mice. J Virol 81:7410–7423 [View Article][PubMed]
RockxB.,
BriningD.,
KramerJ.,
CallisonJ.,
EbiharaH.,
MansfieldK.,
FeldmannH.2011; Clinical outcome of henipavirus infection in hamsters is determined by the route and dose of infection. J Virol 85:7658–7671 [View Article][PubMed]
TaubD. D.,
LloydA. R.,
ConlonK.,
WangJ. M.,
OrtaldoJ. R.,
HaradaA.,
MatsushimaK.,
KelvinD. J.,
OppenheimJ. J.1993; Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med 177:1809–1814 [View Article][PubMed]
ValbuenaG.,
HallidayH.,
BorisevichV.,
GoezY.,
RockxB.2014; A human lung xenograft mouse model of Nipah virus infection. PLoS Pathog 10:e1004063 [View Article][PubMed]
WeissenbachM.,
ClahsenT.,
WeberC.,
SpitzerD.,
WirthD.,
VestweberD.,
HeinrichP. C.,
SchaperF.2004; Interleukin-6 is a direct mediator of T cell migration. Eur J Immunol 34:2895–2906 [View Article][PubMed]