Host cell receptor for virus

Try out PMC Labs and tell us what you think. Learn More. The interaction of the hemagglutinin HA of the influenza A viruses IAV with the cell surface is a key factor for entry of the virus and productive infection of the cell. However, due to the ability of the HA of avian, swine, or human influenza viruses to bind differently linked SA and also to the high levels and variability of glycosylations of their major virion glycoprotein components, HA and NA, IAV interacting proteins on the cell surface could also play an important role in initiating different signaling pathways to elicit the immune response in infected cells.

But, at present, these processes are not well understood. In this mini-review we discuss how the interactions of IAV with cell surface receptors on immune cells might be important for the induction of specific innate immune responses and as a result, for pathogenicity in humans. Influenza viruses are an important threat to human health and global economy, causing an annual average of 36, deaths and over , hospitalizations during the s CDC, In addition, due to the high frequency of mutations and recombination of their genome antigenic drift and shift , and their airborne transmission, they have a high potential to become pandemic viruses.

Influenza viruses belong to the family Orthomyxoviridae, and include the types, A, B, and C, from which influenza A viruses IAV are the responsible for most of the disease burden Mubareka and Palese, The major glycoproteins present on the surface of the virion are the hemagglutinin HA and the neuraminidase NA.

To date, 16 HA and 9 NA subtypes have been described, and the combination of different subtypes of these proteins results in different subtypes of IAV Mubareka and Palese, The main roles of the HA are to mediate the interaction of the viral particle with the cell components on the surface and to promote the fusion of the viral and endosomal membranes, leading to the release of the ribonucleoproteins RNP into the cytoplasm.

The interaction of influenza viruses with their receptors is necessary for subsequent internalization of the virus. Some studies demonstrated that IAV enter the cell via clathrin mediated endocytosis, although under certain conditions they can also enter in a caveolin and clathrin independent manner Lakadamyali et al. Here we review and discuss how the interaction of IAV with their receptors on the cell surface of immune cells, such as dendritic cells DCs and macrophages, might influence infection and promote specific innate immune responses, with important implications in the outcome of the disease, either promoting viral clearance or generating exacerbated local immune responses resulting in acute infection and increased pathogenesis.

The circulation of IAV is species-specific, and therefore, transmission among different species is usually not observed. It is known that the receptor specificity has an important role in maintaining the host species barrier, although other proteins, like PB2, also need to be adapted for efficient infection of other hosts different than the original host Almond, ; Neumann and Kawaoka, Sialic acids SA, N -acetylneuraminic acid are the primary receptors for virus attachment to cell surfaces, binding to a pocket at the distal tip of the HA of IAV Weis et al.

Humans infected with H5N1 present unusually high serum concentrations of chemokines and pro-inflammatory cytokines, which are thought to contribute to disease severity Peiris et al. Therefore, the receptor specificity of influenza viruses is important not only for the host tropism, but also for tissue tropism in humans, since it determines the airway region and cell types that support active viral replication, what might contribute to the severity of the disease observed in humans infected with HPAIV.

Moreover, a recent work by Watanabe et al. It is believed that modifications in the receptor specificity of avian H5N1 influenza virus would be necessary to allow human-to-human direct transmission Enserink, ; Tumpey et al. The development of glycan arrays has provided highly valuable information regarding the receptor binding specificity of the HA of numerous IAV isolates Stevens et al. In the last few years, numerous studies have provided increasing evidence for a role for the viral HA—SA interaction in the induction of innate immunity and pathogenesis.

SA are structural components of the cell surface, and they have important implications in the immune responses Crocker and Varki, ; Videira et al. On the other hand, DCs are essential players in the induction of innate immunity, as well as in the initiation of adaptive responses.

Upon sensing invading pathogens via several pattern recognition receptors PRRs , they differentiate to mature DCs and migrate to the secondary lymphoid organs, where they present the processed antigen to T-lymphocytes.

Additionally, it has also been shown that the elimination of the SA from the surface using a sialidase induced the maturation and activation of human DCs Crespo et al.

These last studies reinforce the idea of a role for SA in immunity, and also could have implications in the immune responses against IAV, as the IAV NA is one important component of viral particles. One of the first reports suggesting the importance of HA—SA interaction in eliciting innate immune responses was published by Miller and Anders , who showed that inactivated IAV are able to induce type I IFN production in mouse spleen cells in a SA-dependent manner.

Several studies have been performed comparing cytokine responses between avian H5N1 viruses and human H1N1 in immune and epithelial cells, and most were able to demonstrate that the H5N1 IAV induced the strongest production of cytokines and chemokines, as compared to H1N1 IAV Cheung et al. However, the viral factors responsible for this effect were not clearly determined, due to high disparity in the viral segments among the strains compared, and it is likely that a combination of them HA, NS1, PB1-F2… could account for these differences.

In order to elucidate if differences in receptor specificity of the IAV are important for this hyper-induction of pro-inflammatory cytokines, we recently reported that recombinant viruses bearing the HA and NA from a HPAIV H5N1, which differed only in two amino-acids that were shown to modify receptor specificity, induced different cytokine profiles in human DCs, macrophages, and primary bronchial—epithelial cells Ramos et al.

Using these viruses with identical genes with the exception of two amino-acids in the HA we could clearly analyze the contribution of this important factor to the immune responses in human immune cells. However, human IAV detection would result in delayed induction of cytokines.

At that stage of infection, IAV proteins involved in innate immune evasion such as NS1 or PB1-F2 could antagonize innate immunity, resulting in lower expression of pro-inflammatory cytokines. Model for recognition of human and avian IAV by human immune cells. IIA, innate immunity antagonists. In this work, no clear differences were observed between H5 and H1 HAs, but it is important to note that the cytokine profile induced in murine DCs could differ of that observed in human DCs, probably due to different sialylation patterns in those two systems.

Interestingly, Eierhoff et al. Furthermore, they observed recruitment of the regulatory subunit p85 of PI3K to the EGFR in response to viral attachment, indicating activation of downstream signaling pathways, which are necessary for endocytosis triggering. These results are of great relevance, indicating that the interaction of the viral particles with the cell surface via RTK might have important impact not only in viral uptake, as the authors demonstrated, but its activation could play a role also in the innate immune response to IAV, since it is known that the EGFR pathway is involved in the production of IL-8 by respiratory epithelial cells, resulting in neutrophils recruitment in airway inflammatory diseases Subauste and Proud, ; Nakanaga et al.

Influenza A viruses are recognized by different PRRs in host cells, leading to the initiation of the innate immune response aimed to defeat the virus. Summary of cell surface or soluble host molecules reported to interact with IAV. Attachment events facilitate phagocytosis, and also induce the activation of several signaling pathways that modulate immune responses to that pathogen Geijtenbeek and Gringhuis, Dendritic cell-specific intercellular adhesion moleculegrabbing non-integrin DC-SIGN is one of the best-characterized CLRs, which is expressed in immature DCs and recognizes and binds to high mannose containing glycoproteins, commonly found in several pathogens, including viruses.

Gonzalez et al. On the other hand, the mannose binding lectin MBL , which is a soluble PRR belonging to the collectins family, is known to have anti-IAV activity, since it inhibits hemagglutination, resulting in viral neutralization, opsonizes viral particles allowing for better recognition and ingestion by phagocytic cells, and also activates the lectin complement pathway Kawai et al.

The IAV interaction with surface cellular receptors is important for the pathogenesis and the immune responses generated in the host. The receptor specificity of IAV is determinant for allowing entry in the cell, and differential SA specificity accounts for host and cell tropism. Several specific cell receptors have been identified to interact with IAV in a SA-dependent or independent way. Vaccine or laboratory strains of measles virus have been adapted to grow in common cell lines such as Vero and HeLa cells, and were found to use membrane cofactor protein CD46 as a receptor.

CD46 is a regulator that normally prevents cells from complement-mediated self-destruction, and is found on the surface of all human cells, with the exception of erythrocytes. Mutations in the H protein, which occur during adaptation and allow the virus to use CD46 as a receptor, have been identified. Wild-type isolates of measles virus cannot use the CD46 receptor. SLAMF1 is found on activated B, T, dendritic, and monocyte cells, and is the initial target for infections by measles virus.

These findings suggest that a neurotransmitter receptor or a closely associated molecule may serve as a specific host cell receptor for rabies virus and thus may be responsible for the tissue tropism exhibited by this virus. In addition to clarifying aspects of rabies virus pathogenesis, these studies have broad implications regarding the mechanism by which other viruses or viral immunizations might mediate autoimmune diseases such as myasthenia gravis.

Abstract Characterization of specific host cell receptors for enveloped viruses is a difficult problem because many enveloped viruses bind to a variety of substrates which are not obviously related to tissue tropisms in the intact host. Publication types Research Support, U. Gov't, Non-P.