hantavirus mechanism of infection

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  • Mar 27, 2020

Mechanisms of vasculopathy in hantavirus infections. The ...
Mechanisms of vasculopathy in hantavirus infections. The …

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Hantaviruses, like other members of the family Bunyaviridae, emerging virus that causes dengue fever. occasional transmission to humans is due to inhalation of aerosols contaminated with feces from an infected rodent. Hantaviruses no symptoms in rodents or insectivores their natural hosts with which they have co-evolved over millions of years. Instead, hantaviruses cause different pathologies in humans with a mortality rate varies, depending on the hantavirus species and geographic origin. Cases of dengue fever with renal syndrome (HFRS) has been reported in Europe and Asia, while hantavirus cardiopulmonary syndrome (HCP) were observed in the United States. In some cases, the disease caused by hantaviruses Old World shows HCP-like symptoms. Although the etiologic agent of HFRS identified in the early 1980s, hantaviruses way to interact with different hosts remains elusive. What receptors in? How hantaviruses spread in the organism and how they cope with the immune system? This review summarizes recent data documenting the interaction established by hantaviruses pathogenic and non-pathogenic by nature or human host they can highlight different results.

Hantaviruses the tri-segmented, enveloped, RNA virus of negative polarity, belonging to the family Bunyaviridae. Unlike the members of four other genera, viruses of the genus Hantavirus not arthropod-borne. their human transmission occurs through inhalation of virus aerosol particles present in the dried feces of infected rodents naturally, among others, hantaviruses circulating without providing recognized symptoms. human pathology associated with hantaviruses have been observed since 1950, with documentation Dengue Korea, but the virus Hantaan (HTNV) isolated from the prototype only striped field mouse (Apodemus agrarius) in 1978 [,]. For now, only hantaviruses circulating among rodent reservoirs (Murinae, Arvicolinae, and Sigmodontinae) has been found to be pathogenic to humans.

new hantaviruses are now described in a lot of small insect-eating mammals [], like moles and mice (Soricomorpha), and at bats (Chiroptera). A recent study conducted in Brazil showed their bats hantaviruses between the different bat species, and not solely on insectivorous bats as previously suggested []. This discovery points to the fact that hantaviruses circulating in the reservoir hosts throughout the world, expanding the possible risk of co-infection by a host of different hantaviruses, and therefore reassortment virus and host of spill-over. In addition, the reservoir ecological change due to human impacts on climate and biodiversity is an additional factor that makes hantaviruses global public health concern [,].

Since their initial discovery, more than 20 different species of hantaviruses are pathogenic to humans has been described, with new viruses regularly found throughout the world. They cause hemorrhagic fever with renal syndrome (HFRS) in the Old World (Europe and Asia) while hantavirus cardiopulmonary syndrome (HCP) is more specifically associated with human illness in the New World (America). The main HFRS symptoms are acute kidney injury (AKI) and dengue fever.

The most frequent hantavirus, endemic to European countries, is the Puumala virus (PUUV), caused more than 10,000 cases each year nephropathia epidemica. A mild form of HFRS has a case fatality of less than 0.2%. However, mortality associated with Dobrava virus (DOBV) in Central Europe, and HTNV or Seoul virus (SEOV) in Asia can reach 15%. It is mention worthy that SEOV have recently been described in wild rodents and pets in some European countries [,,,] and that some human cases have also been detected in the United Kingdom and France [,]. Easy adaptation of rats to other areas, in urban areas in particular, has led to an extension SEOV outside Asia. In the USA, HCPs gifts with pulmonary edema, and although the cases are less frequent (hundreds per year), hantaviruses, such as viruses Andes (ANDV) in South America and the virus Sin Nombre (SNV) in the US, may lead to a mortality rate of 50% of an infected person. Although clinical photographs variable [,], which depends on hantavirus and geographical origin, HFRS and HCP share a common characteristics. In particular, thrombocytopenia [,] and leakage of blood vessels [,] to correlate with disease severity. These features have been compared with the different forms of dengue fever presents a similar clinical manifestations [].

Many of the questions regarding the mechanism of transmission and pathogenesis in humans, and how to deploy on individual hantaviruses (entry, tropism and target organs for the disease) remain to be answered. Understanding how hantaviruses interact with specific host factors can explain: (a) the degree of pathogenicity observed in humans vary, from non-pathogenic to nephropathia epidemica, HFRS or HCP; and (b) how the situation constantly and without symptoms achieved in the natural universe. The latest limited review has discussed hantavirus pathogenesis [,], hantavirus interaction with the immune system [,,], or their persistence in rodents [,]. These topics will not be detailed here. Instead, this review summarizes information on factors pathogens, as inferred from comparison of the effects of pathogens than pathogenic hantaviruses in humans and natural hosts. A better understanding of the mechanisms that lead to a different result hantavirus should throw some light on this virus physiopathology and helps to identify factors pathogenesis that could represent a potential therapeutic target.

Although hantaviruses have no symptoms in rodent reservoirs, they are very viremik and seroconversion takes place in the host of this nature, as demonstrated by the production of antibodies, including neutralizing antibodies. Recent data using laboratory animals indicate that the phase viremik on wild rodents longer than previously described []. The virus is found in many organs, such as kidneys, liver, spleen, heart, and in larger quantities, lungs. However, these types of infected cells in each tissue or organ is not always determined. The virus is also found in saliva, urine and feces of rodents [], and can last for several weeks in the environment [], which increases the risk of transmission to humans. Variations in the rate of viral shedding was observed depending on the species of hantavirus. Hantaviruses replicate in natural hosts despite the adaptive immune response. This raises the question of tolerance and resistance balanced manner in the host rodent as hantaviruses escape of innate and adaptive immunity and establish a persistent state without omitted.

In contrast to what is observed in rodents, human hantavirus infections can cause clinical signs. Similar to some other human pathogen causing dengue, endothelial cells are the main target of hantavirus infection []. In HFRS patients and HCPs, endothelial cells were infected ubiquitously throughout the body, although the injury is most pronounced in the lungs and kidneys. The non-lytic infection, but the functionality is changing the infected endothelial contribute to increased permeability of blood vessels, bleeding, pulmonary edemas thrombocytopenia and acute renal failure as described for hantavirus disease [].

The specificity of the host narrower than hantaviruses, with species of the virus adapted to one species of rodent, and the fact that the mice experienced host does not harbor any obvious symptoms, making it difficult to develop animal models to study the physiopathology of this virus. Several studies have been conducted using a rat model of the disease hantavirus carried by hamsters Turkey [] or Syrian hamster, where only the New World hantaviruses pathogen induces symptoms resembling HCP [,]. However, a recent report showed that the virus Imjin (MJNV) held by some Asian Rat able to induce pulmonary syndrome in Syrian hamsters []. Best animal models remain on nonhuman primates apes for both New and Old World hantaviruses [,,]. Recent data described the possibility of infection with hantaviruses humanized SCID mice []. Today, most of the data on the physiopathology of hantaviruses derived from analysis of human clinical samples, or samples of reservoir host, as well as from in vitro studies with cell models.

The underlying mechanism of the main symptoms of vascular permeability observed in both HFRS and HCP are not fully understood. In particular, the endothelial cells are not directly aligned by hantavirus infection. The current hypothesis to explain the vascular leakage is that the exaggerated innate immune response that could disrupt the barrier function of the endothelium [,]. It was thenproposes that the infected endothelial cells of the lungs or kidneys will secrete factors that lead to the recruitment of innate immune cells (macrophages, dendritic cells, neutrophils, T cells). Recruited immune cells, in turn, will secrete pro-inflammatory cytokines upon activation, affecting the integrity of the barrier. In addition, macrophages can be infected by hantaviruses, which will also give inflammatory factors. In addition, many studies of HCP have highlighted the role of vascular endothelial growth factor in the regulation of vascular permeability, as well as the following hypoxia [].

While the pathogenic hantaviruses do not always cause severe disease, some serological evidence has been obtained for human infection with hantaviruses that are considered pathogenic, such as Prospect Hill (PHV) or Tula (TULV) virus [,]. Additional epidemiological study is needed to clarify whether or not hantaviruses rodent or insectivore-borne pathogenic others might emulate in humans. Understanding how different viruses interact with humans and small mammals that are infected endothelial dysfunction with or without saving is very important. It would be very interesting to investigate whether the same mechanism operates in rodents and in humans infected asymptomatic pathogenic hantaviruses.

To date, no human-human transmission was observed from hantaviruses [], except in a few cases are caused by ADNV HCP []. Although the bite between the fighting men may be a mode of transmission among rodents, the main portal to enter into mice and humans Hantavirus is a virus inhale aerosol. For subsequent maintenance and transmission between individuals, the virus must replicate in the target cells, and then spread from the lungs to other organs, and then must be shed.

It is of interest to evaluate whether or not the difference can be found in the way of each species of hantavirus infects cells in the main target. virus envelope glycoprotein, Gn and Gc, plays an important role in the process of targeting these receptors interact with specific entries, which can vary according to the hantavirus. Novice virus particles and interaction with cellular factors may also occur in spaces of different intracellular virus during the cycle [].

As described for several other viruses, is strong evidence that cell entry of hantaviruses are mediated by interaction of viral glycoproteins Gn-Gc with integrin. These cell membrane proteins to promote cell and cell-extracellular matrix adhesion. They also induce signaling cascades that regulate cell proliferation, survival, differentiation, activation and migration []. Interestingly, hantaviruses pathogenic and non-pathogenic use different integrin receptors on the surface of human cells: α11β3 used by hantaviruses induce HCP, αvβ3 by hantaviruses stimulate HFRS, and α5β1 by pathogenic hantaviruses [,]. Different cell types express different integrin and β3 chains are abundant endothelial cell surface receptors, dendritic cells (DC) and platelets, which are known to be susceptible to infection hantavirus [,]. In addition, DCs and platelets are involved in blood vessel leakage pathogenic process and thrombocytopenia [].

All hantaviruses β3 integrin pathogens use to enter human cells. It is rather interesting given their diversity and specific associations, each to a host of different nature. However, little information is available on integrin receptors and co-receptors used by the different hantaviruses in rodent reservoirs them. Indeed, the natural reservoir host of hantaviruses are very diverse and the lack of genetic markers and special detection devices make it difficult to identify the receptor or other partners of the interaction in the reservoir hosts. Interestingly, virus Sangassou, an African hantavirus, recently described and shown to interact with the β1 integrin β3 in the reservoir than its Murinae []. It would be interesting to understand whether or not the specificity of the interaction with integrin receptors, and therefore with the target cell type, can affect pathogenesis. In this case, the question of where the cells express the receptor α5β1 pathogenic viruses still have to be addressed. It has been recently demonstrated that hantaviruses can stimulate human neutrophils (PMN) and that β2 integrin receptors that are highly expressed by PMN receptor can act as a new entry[].

Another membrane protein of the complement regulatory system, such as decay-accelerating factor (DAF) for HTNV and PUUV, and gC1qR to HTNV, identified as co-receptors for entry hantavirus [,]. These co-receptors along with integrin may also participate in hantavirus tropism and targeting organ, differentiate pathogenic from pathogenic virus. other cellular proteins, such as the 70 kDa [] and 30 kDa protein [], has also been described to enter HTNV.

Whether or not viral pathogens and non-pathogenic for humans using the same entry receptors in rodents and how these forces impact the virus propagation have not been defined. viral entry is required, but not enough to account for the pathogenesis for both hantaviruses pathogenic and non-pathogenic can infect endothelial cells and macrophages. Therefore, the interaction with intracellular factors involved in viral replication and assembly may also play an important role in the outcome of hantavirus infection.

Envelope glycoprotein that is important to get in, and also in many aspects of the virus trade, maturation and assembly []. Gn interaction with Gc for the formation of spikes that interact with receptors entry, or the interaction of the cytosolic tails of Gn (GnCT) with N nucleocapsid [] required for the assembly of the virus must be finely regulated. Interestingly, the Old and New World hantaviruses shoots on the Golgi membrane or the plasma membrane during virus assembly, respectively. Interestingly, the different functional domains have been identified in GnCT of different hantaviruses. A conserved zinc finger domain support has been found in GnCT interaction of the two viral pathogens, ANDV, and pathogenic, PHV ,. Instead, the signal sequence for degradation by autophagy seems specific to pathogenic hantaviruses []. Such structures could play an important role in virus assembly and pathogenesis. Finally, ITAM domains known to be important for triggering intracellular signal in response to activation of receptors that are present in GnCT of pathogenic hantaviruses associated with HCP. This suggests that deregulation GnCT can participate in the immune and endothelial function [].

In vitro, hantaviruses can infect endothelial cells, epithelial cells, and cells of the immune system, such as macrophages, follicular dendritic cells and lymphocytes through the attachment of the viral glycoproteins to cell-surface receptors in a manner and virus-specific. For example, pathogens, but not pathogenic hantaviruses probably only infect megakaryocytes that have been distinguished []. After infection, the human DC can function as both a vehicle of hantaviruses or allow them to evade the immune system. In addition, the infection induces DC maturation and increased expression of integrin β3, interferon (IFN) -α and tumor necrosis factor (TNF) -α []. Macrophages are the two most important targets of hantaviruses after the endothelial cells in both mice and humans. Although low-level replication and release of infectious virus due to inhibition by IFN-α, monocyte / macrophages from peripheral blood PUUV susceptible to infection [,]. More recently, keratinocytes also been proven permissive to hantavirus infection [], which is interesting considering that hantaviruses can be transmitted by the bite of small mammals.

difficulty in infecting the cell culture with hantaviruses and get a descent virus has caused only fragmentary information about differential mechanism of virus entry, maturation and propagation. Indeed, these studies are complicated by the diversity of rodent and insectivore reservoirs, and at the same time the fine specificity of each hantavirus for one host species. Therefore, the development of new cellular models of the main natural host is very important [] to evaluate the selective factor in different host cells. It will be the only way to understand how networks rodents constantly infected, and why some organ dominated targeted specifically for the pathogenesis of human virus.

It is also acknowledged that hantaviruses are not lytic for their target cells endothelial since there are no signs of cytotoxicity were reported in vitro in primary cells infected efficient including endothelial cells, epithelial, dendritic and mast []. However, the cell damage in patients presenting with nephropathies PUUV manifested by increased levels of perforin, granzyme B, and LDH, as well as epithelial markerscell apoptosis []. There are conflicting reports on whether or not hantaviruses induce apoptosis in vitro. No effect of PUUV recorded on the viability of Vero E6 and A549 cells [], while TULV shown to induce apoptosis in cells VeroE6 []. The effect could depend on the species of viruses and / or type of cell for cytopathic effect of different hantaviruses (HTNV, SEOV, and ANDV) was detected in human HEK293 cells []. More recently, it showed that the N protein of HTNV have antiapoptotic effect in A549 cells and HeLa-mediated down-regulation of p53 []. Although it can be assumed that will not be induced apoptosis in infected cells from mice reservoir, the mechanism of hantavirus persistence in the host of this nature remains to be defined.

Interestingly, recent investigations are in favor of a protective role of cells infected by hantaviruses through two mechanisms that can promote pathogenesis. The first mechanism is to encourage the survival of innate immune cells. As already mentioned, a high level of activation of immune cells could be detrimental. For example, part of the natural killer (NK) cells express receptors NKG2C, specific to human leukocyte antigen (HLA) -E ligand expressed by endothelial cells, expands in patients during acute infection PUUV. Interleukin (IL) -15 and anti-apoptotic molecule Bcl-2 both play a role in promoting the survival of these NK cells proliferate [,]. Similarly, neutrophils are now thought to play an important role in blood vessel leakage was observed on hantavirus disease [] is activated in vitro and in vivo and last longer in response to exposure to hantavirus [,]. We also recently observed prolonged survival of neutrophils as apoptosis is delayed, especially those caused by pathogens PUUV, but interesting, not by TULV pathogenic or PHV hantaviruses (Baychelier, personal communication). The second mechanism is to protect the infected cells from the cytotoxic effects of immune cells. For example, ANDV and HTNV infected endothelial cells resistant to NK cell-mediated murder. As a result, the infected cells will be protected, but non-infected cells around it will not be protected and killed by NK cells [].

Together, the picture is still unclear about the effect on cell viability hantaviruses and how different mechanisms can operate depending on whether hantaviruses are pathogenic or not.

cytokine IFN family is the first defense line of antivirus. virus attack is detected by nonimmune cells early during the infection. Virus molecular recognition by pattern recognition receptors (PRRS), such as Toll-like receptors (TLR) or RIG-I and receptor cytoplasmic helicase MDA5, modulate signaling pathways, or transcription factor, which resulted in the induction of IFN-α / β []. IFNs then induces the expression of a large pattern of IFN-stimulated genes that differed (ISGs) to establish an antiviral state. Additionally, PRRS directly trigger pro-inflammatory response that induces host resistance to infection and activate cells of the innate immune system before the establishment of the adaptive immune response. Among ISGs targeted by a viral infection, ISG15, a ubiquitin homolog, MxA monomer that binds and degrades viral component, RNase L that cuts RNA cellular and viral, and PKR which inhibits phosphorylation of eIF2α factor translation initiation, has been described as directly promote antiviral state [ ].

Hulu type I IFN induction, the expression of TLR4 was shown to be higher in HTNV-infected vein endothelial cells of human (EVC-304) compared to peers who are not infected them, which leads to an increase in IFN-β, IL-6, and TNF-α secretion []. Increased production of IFN-β may provide an antiviral state, while IL-6 is probably responsible for the pro-inflammatory response. Furthermore, TNF-α, which contributes to endothelial permeability, plays a key role in the pathogenesis of HFRS. Indeed, endothelial cell permeability was significantly prolonged in the treatment of TNF-α in HTNV-infected cells compared to uninfected cells []. In the same cellular model of this, an adapter protein that is up-regulated Trif downstream of TLR4 []. Another study, using a human epithelial cell line A549 lung and HuH7 hepatoma cell lines have shown that pathogens HTNV and PHV pathogenic activate the innate immune response in different ways. Both viruses induce IFN signaling through activation Mxa,and, in the case of HTNV, but not PHV, this follows the recruitment of TLR3 []. This finding is consistent with the fact that on endothelial cells, viral pathogens ANDV set early interferon response, whereas the pathogenic PHV not. This may explain how the PHV can infect EC without being able to imitate []. To support this idea, PHV, but not HTNV pathogens, New York 1 virus (NY-1) and ANDV hantaviruses, induce high levels of IFN in human EC early after infection []. However, the situation is more complex because other pathogenic hantavirus (TULV) replicates as successful as pathogens in human ECs showed that TULV also able to regulate the cellular IFN response [].

Type II IFN-γ also show antiviral activity. It has been proven for example, that the pre-treatment of Vero E6 and A549 cells with IFN-γ inhibits HTNV infection dose dependent manner and with MxA-independent mechanism []. However, HTNV already established infection is not sensitive to the subsequent addition of IFN-γ stimulation. The same observation was made for IFN-α / β and IFN-λ []. This observation is consistent with the initial antiviral effects of IFN on viral replication.

Type III IFNs, including IFN-λ1 / IL-29, IFN-λ2 / IL-28A and IFN-λ3 / IL-28B, arranged in a way that is similar to the type I IFN []. The antiviral effect of IFN-λ have been tested in an infected cell. Interestingly, a synergistic effect of inhibition of IFN-λ by IFN-γ, but not with IFN-α / β, shown in HTNV replication in A549 cells []. In line with these findings, high levels of IFN-λ1 HTNV induced in infected A549 cells, and MRC-5, human fibroblast cell line lacking the receptor IFN-λ. The expression of IFN-λ1 preceded the induction of MxA and IFN-β. Moreover, the induction of IFN-λ1 and MxA has been observed in Vero-E6 cells [], which is not the type I IFN and products used to prepare virus stocks. Three New World hantaviruses (SNV, ANDV and PHV) also induce IFN-λ in Vero E6 cell. The presence of IFN-λ in the stock virus was made from the supernatant of cells infected Vero E6, have been shown to activate ISG56 and MxA genes in Huh7 and A549 cells. This happens independently of the virus used to infect these cells, as demonstrated by the neutralization of the effects of using antibodies specific IFN-λ. The situation is different in human umbilical vein endothelial cells (HUVEC) were infected by SNV where induction of IFN-λ of ISGs is virus-specific, and therefore, are not affected by neutralizing antibodies IFN-λ []. This fits well with the fact that HUVEC cells, which do not have the IL-28Rα chain, unable to respond to IFN-λ []. However, the level of IFN-λ decrease in the serum of patients infected PUUV, whereas IFN-α / β levels remained unchanged and IFN-γ elevated. This contradiction could be due to efficient neutralization of IFN-λ by hantaviral protein [].

In order to successfully replicate in cells, viruses have evolved many mechanisms for host defense against IFN-induced in almost every step of signaling pathways []. This is supported by the fact that the pre-treatment of cells with type I IFN-α / β can block replication of hantavirus [,].

transcriptional activation of IFN-β genes requires assembling a enhanceosome containing ATF -2 / c-Jun, IRF-3 / IRF-7, and NF-kB []. N nucleocapsid HTNV block TNF-α induced NF-kB activation by disrupting the nuclear translocation []. This effect is shared by the N protein of DOBV and SEOV, but not of PUUV, SNV and ANDV []. Recently N nucleocapsid of ANDV been shown to carry the virulence can disable PKR domain, and therefore against its antiviral effects [].

S and M segment of some viruses encode proteins bunya nonstructural (NSs and NSM), which can block the transcription of IFN-β as shown for Rift Valley Fever virus NSs []. Since hantaviruses do not have a protein NSs or NSM, these activities should be carried out by one of their four structural proteins (N, Gn, Gc or L polymerase). It should be noted that several hantaviruses, hosted by a rodent of the family Arvicolinae, containing a short conserved open reading frame of evolution. This sequence can encode NSs protein that has been shown to influence the interferon response in cells infected PUUV. It seems unlikely that this NSs is a virulence factor for human infection because it was found in both pathogenic and pathogenic PUUV, hantaviruses TULV and absent of highly pathogenic hantaviruses like ANDV, NY-1, and HTNV [,,].

Gn envelope glycoprotein contains 142 amino acid cytoplasmic tail length (GnCT) involved in the regulation of IFN. A GnCT interaction of pathogens NY-1, but not of PHV, with elements interferon antiviral action of IFN inhibits in endothelial cells []. GnCT recruiting TRAF3 leads to its separation from TBK1. The ubiquitin ligase complex activity which phosphorylates TRAF3-TBK1 IRF3 then eliminated along with the transmission of signals required for transcription of IFN-β [,]. This allows pathogens NY-1 hantavirus, but not pathogenic PHV, to cut the innate immune response and successfully replicate in endothelial cells. Unlike the PHV, which GnCT of pathogenic TULV behave the same as the pathogen NY-1 by inhibiting IFN and responses ISRE is directed upstream of IRF3 on TBK1 complex level. However, unlike the pathogenic hantaviruses, TULV GnCT failed to tie TRAF3 []. GnCT could be a virulence factor responsible for delayed IFN response was observed with NY-1, ANDV and HTNV in infected cells. In line with the important role of IRF3 activation in eliciting IFN response, nuclear translocation of IRF3 impaired in SNV, HTNV and SEOV infection, whereas nuclear accumulation IRF3 seen with PHV pathogenic virus TULV and Thottapalayam []. Strikingly, hantaviruses ability to provoke early IFN response appears necessary for the pathogenesis, but also leads to a different response to two pathogenic hantaviruses, PHV and TULV. The fact that replicates TULV pathogenic succeed in EC, indicates additional viral determinants of pathogenesis [].

Another way to hantaviruses interfere initial innate response, as shown in HTNV infected A549 cells [], could be at the level of STAT1 transcription control signals three types of IFNs. Unexpectedly, the glycoprotein of both ANDV pathogens and pathogenic PHV can inhibit STAT-1 nuclear translocation thus damaging the IFN signaling. Differences in pathogenicity virus can then be based on the different strengths of IRF-3 activation [] in ANDV and PHV infected human lung microvascular endothelial cells (HMVEC-Ls).

A variety of hantavirus infections result it could be related to differential interaction with the initial steps of IFN antiviral pathway. Pathogenesis may result, at least in part, from delayed transcription of IFN-β and other ISGs, allowing pathogenic hantaviruses quickly replicate and spread through the endothelial cell barrier.

Regarding the role of the domain of GnCT and N proteins the virus as a virulence factor, and the fact that hantaviruses are asymptomatic in rodents, one speculation is that the interaction of viral proteins with host factors have different evolves according to background their genetic rodent reservoirs. This could explain why the glycoprotein of hantaviruses behave differently in terms of interaction with elements of the innate immune system that leads to differing degrees of pathogenesis in humans and persistence only in certain natural universe. Overall, these observations indicate the complexity of the mechanisms of protein hantaviral disrupt the innate immune system of different hosts, and suggests the involvement of other processes, such as adaptive immunity.

Hantaviruses that viremik in humans and in rodents, and neutralizing antibodies are produced in both cases. Human antibodies protect against re-infection, but it certainly did not hurt virus circulation and persistence in rodents. This phenomenon can not be easily explained and differential role of T cells has been proposed.

NK cells are on the border between innate and adaptive immunity. In pathogenic conditions, they rapidly expand and then persist during acute infection in humans, with their number of residual elevated for at least 60 days. A strong T cell responses involving CD8 + cytotoxic lymphocytes, and to a lesser extent CD4 + T cells, also accompanies the acute phase of infection PUUV []. A mixed pattern of T cells of Th1 and Th2 phenotype as well as high levels of pro-inflammatory cytokines, are not efficiently suppressed by regulatory cytokines, causing harmful effects on the infected patient []. After that, the T cells decreased with the decrease in viral load and clearance of viremia which may be causedfor negative signal effect of intrinsic and extrinsic regulation.

It is hypothesized that CD4 + regulatory T cells (Treg) can explain the persistence of the virus in rodents [], while the NK and CTL has a role to play in human pathogenesis. Currently, the induction of FoxP3 + regulatory CD8 + or CD4 + T cells have not been detected in patients during acute hantavirus infection. However, CD8 + cells and CD4 + T can modulate effector responses through different inhibitory receptors during acute viral infection []. It is estimated that hantavirus infection induces DC differentiation, and then antigen-presenting cells (APC) transition and T cell stimulation In particular, the induction of memory T cells with durable protection found in infected patients []. the results of different infections in humans and rodents can be explained by the fact that the T-CD8 + interested infected endothelium would damage in humans, whereas in rodents, these T cells are turned off by the induction of Tregs. However, this image is a simplification because PUUV-induced increase in the severity of nephropathia epidemica correlated with higher levels of FoxP3 + Treg [].

The importance of T cell responses is also evidenced by the fact that a large response to hantaviruses against CD8 + T cell epitopes restricted immunogenic HLA-I []. In this case, hantavirus infection in distinct cell types up-regulate the expression of HLA-I, which is involved in antigen presentation, as well as the DC cross-presentation to CD8 + T cells [].

As already mentioned, little is known about how hantaviruses can replicate and persist in small reservoirs mammal species although induced seroconversion and high titers of antibodies in the host’s natural. Of note, the epitopes on the N and Gn structural proteins recognized by antibodies induced in rodents are different from that induces a human antibody reactivity. Instead, three epitopes from Gc protein that is immunogenic in both humans and rodents. Each hantavirus species also show a narrow specificity for a particular reservoir hosts and little is known about the mechanisms that limit spill and adaptation of new mammals. It has been proven that deer mice, natural host SNV pathogens, can be infected by ANDV, which is also very pathogenic to humans and no symptoms in its host reservoir, pygmy rice rat. In both the case of virus infection, the infected endothelial cells, but deer mice did not present obvious symptoms. However, ANDV not maintained in deer mice, while SNV remain in his or her particular host. Interestingly, the deer mouse immune response to infection is different depending on the hantavirus. Persistence of SNV associated with low induction of immune cells. Conversely, heterologous ANDV cleared after a strong induction of B and T cell immune response []. This phenomenon must be the consequence of long-term evolution and adaptation rodents hantaviruses with their natural host [].

Despite the differences have been noted in the case of entry receptor, interaction partners and modulation of interferon response, a clear representation of the differences that lead to different levels of pathogenicity associated with hantaviruses have not been obtained. This is not surprising given the complexity of the signaling cascade downstream from the IFN, which can be triggered in situations different innate immunity. In addition, the level of interferon and their receptors will depend on the cell type, such as IFN-λ receptors are only expressed on epithelial cells. In addition, the IFN signaling is linked to other cellular processes such that during the formation of hantavirus disease, pro-inflammatory events also impact the process of coagulation and permeability of blood vessels as well as in the recruitment of cells of both innate and adaptive immunity.

Studies using high throughput or multiplex technology reveals more complexity. For example, in one study using serum SNV-infected patients with HCP, the levels of specific cytokines from Th1 and Th2 responses varied, rising revealed in IL-6, IFN-γ, TNF-α sIL2R and is accompanied by a decrease in IL-10 []. In another analysis, 68 different cytokines, including chemokines factors, angiogenic and growth, were tested. Important changes are mostly up-regulation of IL-6, CXCL10, CX3CL11, MIF and MIG, and down-regulation of CXCL12 and tutoring aser far as CCL21, 22, 27 and sCD40L []. This up-regulation of cytokine expression, can promote tissue migration of mononuclear cells (lymphocytes T, NK and DC), with leukocytes play a role in the repair of lung tissue, as well as in improving the endothelial monolayer permeability. By contrast, down-regulation of cytokines associated with platelet homeostasis consistent with thrombocytopenia was observed in patients.

For the HFRS patients, serum levels of IFN-γ, IL-10, CCL2, and IL-12 has been shown to up-regulated compared to healthy controls. Then depending on the phase variation and severity of the disease, with IFN-γ and IL-12 were associated with a mild form []. Up-regulation of Upar also been described in patients PUUV. These receptors bind to β3-integrin and can lead to proteinuria by acting on the kidney glomerular endothelium []. As for HCPs, a significant elevation of IL-6 and TNF-α plasma levels and also of IL-10 has been detected in the early phase of acute HFRS []. In addition to the factors involved in renal failure (creatinine, C-reactive protein and NO), up-regulation of inflammatory cytokines has been confirmed in a monkey model of infection PUUV []. Increased CXCL10 also been described in the serum of patients infected by HTNV depending on the severity of the disease []. More recently, the factors associated with inflammation or coagulation such as tPA and PAI-1 has also been found in the serum of both patients and monkeys experimentally infected HFRS PUUV [].

There is a striking difference in the initial induction ISGs in HUVEC which was infected with both pathogens causing hantaviruses HCP (NY-1) and HFRS (HTNV) or non-pathogenic hantavirus PHV. suppress pathogenic virus whereas IFN response PHV activate pathogenic response. Induction of IL-6, IL-8, and adhesion molecules involved in leukocyte recruitment appears on viral pathogens []. A similar transcriptional analysis reveals the different impact of SNV pathogens and pathogenic PHV on vascular endothelial cells []. In particular, among other genes, CCL5 and CXCL10 looked specifically up-regulated by the SNV. HUVEC human cells infected by HTNV, also showed increased CCL5 and IL-6 as well as the induction of molecules ICAM-1 and VCAM-1 adhesion []. A cytokines and receptors has been carried out with the primary screen DC infected by ANDV. It revealed the induction of pro-inflammatory cytokines between IL-10 and matrix metalloprotease, MMP9, can indirectly affect HUVEC endothelial cell permeability []. THP1 HUVEC endothelial cells and macrophages have been used for microarray analysis. Muskrat borne pathogenic influence (MJNV and Thottapalaiam virus) and rat-borne (PHV) as compared to HTNV pathogenic hantaviruses. Currently, there are no human disease has been associated with hantaviruses circulating in insectivores. It is worth considering that MJNV and Thottapalaiam virus, are considered pathogenic to humans, it may lead to pro-inflammatory cytokines such as HTNV, but not PHV []. Also, as already mentioned, MJNV cause disease in the Syrian hamster model of []. This could represent a risk of human hantaviruses from reservoirs in addition to mice and requires further attention.

differential regulation of the innate immune response by hantaviruses pathogenic and non-pathogenic been evaluated in models of other cells. The fact that the chemokine CCL5 and activated in A549 cells infected by HTNV HuH7 but not by PHV, indicating the involvement of different waterfalls downstream signaling []. Proteomics has revealed high levels of CXCL10 activation in cells infected HuH7 PUUV, compared with the control uninfected cells or cells infected with pathogenic TULV or PHV (our unpublished data). CCL5 and CXCL10 are also up-regulated in keratinocytes derived cells vulnerable to HTNV [].

It has been reported that the pattern of expression of non-coding single-stranded miRNA gene regulators, differ in response to pathogens (HTNV) vs. non-pathogenic (PHV) hantaviruses []. This differential expression occurs in HUVEC endothelial, epithelial A549 THP1 macrophages or human cell lines, the cell-type specific manner. Moreover, the expression of several miRNAs involved in the regulation of active protein during the innate immune response including Mxa, IP-10 (CXCL10), INF-β or RANTES (CCL5), varies inverselyly in HTNV and PHV-infected cells. differentially expressed miRNAs also targets the immune receptor signaling by RIG-I-like, NOD-like, Toll-like receptors and inflammatory pathways including the JAK-STAT, PI3K-Akt and MAPK signaling pathways. It has also been demonstrated that infection alters the expression of several miRNAs ANDV EC specifically involved in blood vessel integrity, compliance and angiogenesis []

It is important to understand the mechanisms that explain :. (A) one hantavirus persistence and specificity for a given host species; (B) whether or not the spill-over of hantaviruses can occur between species; and (c) if the spill can result in switching over the host, that is, the adaptation to the new host.

As already mentioned, SNV persistent in the natural host, the mouse deer, which are also susceptible to experimental infection by ANDV. Gene expression analysis in real-time quantitative PCR arrays has shown that these two viruses interact differently with the factor of lymph node cells from infected deer mice []. Coherent expression profile by means of B and T cells induces persistence or clearance SNV ANDV []. For example, Th2 and IL-4 signaling factor that is upregulated in ANDV infected mice, whereas according to the Th1 cytokines and Treg phenotype dominant with SNV. Treg activation has also been reported in Norway rats, SEOV natural reservoir host, and can contribute to persistence. In such situations, pro-inflammatory mediators is not enabled [].

Together, these data highlight the importance of the innate immune response in a different outcome of hantavirus infection (pathogenic vs. non-pathogenic or persistent). The complexity of the balance between the different signaling networks that regulate cell homeostasis and infection after study time, may contribute to the variability of results obtained in different cellular models.

The mechanism of maintaining hantavirus pathogenesis in humans or animals leading persistence in reservoirs most likely the result of the interaction of hantaviruses by the immune system. A lot of data has been collected, however, still much to be understood before a comprehensive synthesis can be established. Arguments gathered in the role of mediators of inflammation and immune cells targeting the endothelium during pathogenesis. However, some differences exist and may be due to the limitations of cellular models, how hantaviruses are produced in vitro, or the post-infection period of observation. Transcriptome or proteome analysis supports the existence of differences in the relationship hantaviruses pathogenic and non-pathogenic to a different host. The data obtained so far on good terms with some of the markers of clinical pathogens. This large-scale approach will allow for the comparative experiment using different viruses in different cell models. This technology will be the basis for the discovery of the underlying mechanisms of these different ways to manipulate the virus appeared antiviral responses and disrupt cellular function. In addition, this technology will also help to identify certain factors that can be targeted to neutralize pathogenesis and designing specific therapies.

This work was supported by the European Program FP7 Antigone n ° 278 976. The contents of this publication are those of the authors and do not necessarily reflect the views of the European Commission. The authors thank Stuart Moore to carefully read the manuscript and suggestions.

M.E. and F.B. compile bibliographical references and write a review and all authors contributed to the discussion about the content review. All authors have read and approved the final manuscript.

The authors declare no conflict of interest.

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