The Epidermal Growth Factor Receptor (EGFR) Promotes Uptake of Influenza A Viruses (IAV) into Host Cells

Development of pneumonia is the most lethal consequence of influenza, increasing mortality more than 50-fold compared with uncomplicated infection. The spread of viral infection from conducting airways to the alveolar epithelium is therefore a pivotal event in influenza pathogenesis. We found that mitogenic stimulation with keratinocyte growth factor (KGF) markedly accelerated mortality after infectious challenge with influenza A virus (IAV). Coadministration of KGF with IAV markedly accelerated the spread of viral infection from the airways to alveoli compared with challenge with IAV alone, based on spatial and temporal analyses of viral nucleoprotein staining of lung tissue sections and dissociated lung cells. To better define the temporal relationship between KGF administration and susceptibility to IAV infection in vivo, we administered KGF 120, 48, 24, and 0 h before intrapulmonary IAV challenge and assessed the percentages of proliferating and IAV-infected, alveolar type II (AECII) cells in dispersed lung cell populations. Peak AECII infectivity coincided with the timing of KGF administration that also induced peak AECII proliferation. AECII from mice that were given intrapulmonary KGF before isolation and then infected with IAV ex vivo exhibited the same temporal pattern of proliferation and infectious susceptibility. KGF-induced increases in mortality, AECII proliferation, and enhanced IAV susceptibility were all reversed by pretreatment of the animals with the mTOR inhibitor rapamycin before mitogenic stimulation. Taken together, these data suggest mTOR signalingdependent, mitogenic conditioning of AECII is a determinant of host susceptibility to infection with IAV. viral pneumonia | influenza A | alveolar epithelial type II | mitogen | mTOR

Section: Discussionmentioning

confidence: 99%

Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection

Nikolaidis

Noel²,

Pitstick

et al. 2017

“…For example, EGFR mediates the uptake of cytomegalovirus by monocytes and influenza A virus by epithelial cells (18,19). Also, HER2 signaling stimulates endothelial cell invasion by Neisseria meningitidis and neuronal demyelination in response to Mycobacterium leprae (20,21).…”

Section: Discussionmentioning

confidence: 99%

EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

Zhu

Phan

Boontheung

et al. 2012

152

191

The fungus Candida albicans is the major cause of oropharyngeal candidiasis (OPC). A key feature of this disease is fungal invasion of oral epithelial cells, a process that can occur by active penetration and fungal-induced endocytosis. Two invasins, Als3 and Ssa1, induce epithelial cell endocytosis of C. albicans, in part by binding to E-cadherin. However, inhibition of E-cadherin function only partially reduces C. albicans endocytosis, suggesting that there are additional epithelial cell receptors for this organism. Here, we show that the EGF receptor (EGFR) and HER2 function cooperatively to induce the endocytosis of C. albicans hyphae. EGFR and HER2 interact with C. albicans in an Als3-and Ssa1-dependent manner, and this interaction induces receptor autophosphorylation. Signaling through both EGFR and HER2 is required for maximal epithelial cell endocytosis of C. albicans in vitro. Importantly, oral infection with C. albicans stimulates the phosphorylation of EGFR and HER2 in the oral mucosa of mice, and treatment with a dual EGFR and HER2 kinase inhibitor significantly decreases this phosphorylation and reduces the severity of OPC. These results show the importance of EGFR and HER2 signaling in the pathogenesis of OPC and indicate the feasibility of treating candidal infections by targeting the host cell receptors with which the fungus interacts.

“…Recently, IAV entry was shown to involve the activation of tyrosine kinase growth factor receptor signaling on virus binding (6). The macropinocytosis-like entry route induced in the presence of serum was found to be specifically sensitive to inhibitors of tyrosine kinase growth factor receptors (3).…”

Section: Discussionmentioning

confidence: 99%

Influenza A virus entry into cells lacking sialylated N-glycans

Vries

Wienholts

et al. 2012

Influenza A virus (IAV) enters host cells after attachment of its hemagglutinin (HA) to surface-exposed sialic acid. Sialylated Nlinked glycans have been reported to be essential for IAV entry [Chu VC, Whittaker GR (2004) Proc Natl Acad Sci USA 102:18153-18158], thereby implicating the requirement for proteinaceous receptors in IAV entry. Here we show, using different N-acetylglucosaminyl transferase 1 (GnT1)-deficient cells, that N-linked sialosides can mediate, but are not required for, entry of IAV. Entry into GnT1-deficient cells was fully dependent on sialic acid. Although macropinocytic entry appeared to be affected by the absence of sialylated N-glycans, dynamin-dependent entry was not affected at all. However, binding of HA to GnT1-deficient cells and subsequent entry of IAV were reduced by the presence of serum, which could be reversed by back-transfection of a GnT1-encoding plasmid. The inhibitory effect of serum was significantly increased by inhibition of the viral receptor-destroying enzyme neuraminidase (NA). Our results indicate that decoy receptors on soluble serum factors compete with cell surface receptors for binding to HA in the absence of sialylated N-glycans at the cell surface. This competition is particularly disturbed by the additional presence of NA inhibitors, resulting in strongly reduced IAV entry. Our results indicate that the balance between HA and NA is important not only for virion release, but also for entry into cells. (IAV) is an enveloped, negative-strand RNA virus that causes respiratory and/or intestinal infections in a variety of animal hosts, including birds and mammals. The IAV envelope contains two glycoproteins: the hemagglutinin (HA) protein, which is responsible for virus cell attachment and fusion, and the neuraminidase (NA) protein, which is the receptordestroying enzyme essential for release of the virus from the host cell after budding. IAV attaches to host cells by binding of HA to sialic acids (SIA) present on the host cell surface. Attachment is followed by entry via endocytic routes delivering the virus to the acidic environment of the late endosome that triggers HA-mediated fusion. The interactions of HA with SIA likely are important determinants not only of attachment, but also of virus uptake, intracellular trafficking, and fusion.Cell surface glycan composition is complex and varies between host and cell type. Sialylated glycans are attached to membrane phospolipids or to membrane proteins via asparagine (N-linked glycans) or serine/threonine (O-linked glycans) residues. How and to what extent binding of IAV to specific sialoglycans determines subsequent endocytosis remains unclear. N-linked glycans have been shown to be required for IAV entry, even though O-linked glycans and/or glycolipids permit efficient sialic acid-dependent binding of IAV to cells devoid of sialylated N-linked glycans (2). Thus, it appears that beyond the well-established requirement for binding to either α2-6 SIAs of human IAVs or α2-3 SIAs of avian IAVs, a specific subset of glyc...