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Viruses 2012, 4(10), 2182-2196; doi:10.3390/v4102182
Published: 17 October 2012
Abstract: The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread. Here, we will discuss both the host’s response to infection with data from human infection and lessons learned from animal models, as well as the multitude of ways the virus combats the resulting immune response. Finally, we will highlight recent work identifying TLR2 as an innate sensor for arenaviruses and how the TLR2-dependent response differs depending on the pathogenicity of the strain.
Old World arenaviruses cause a wide spectrum of disease in humans, determined by the strain of virus and the immune status of the patient. Lassa virus (LASV) affects an estimated 2 million people each year, causing mild, flu-like illness to severe multisystem disease. Lymphocytic choriomeningitis virus (LCMV) generally causes a mild, self-limiting illness in the immunocompetent person with rare progression to severe or fatal encephalitis, but can cause a hemorrhagic fever-like disease in patients in which the virus was acquired through solid organ transplantation, and are thus immunocompromised.
Because of strict regulations, studies involving LASV can be quite cumbersome. Since the earliest symptoms of LASV infection are non-specific, patient data is unreliable and incomplete. In order to understand the immune responses that contribute to LASV pathogenesis, or lack thereof, the use of surrogate arenaviruses, both Old and New World, in cell culture and animal model experiments helps to build a better picture of how Old World arenaviruses can cause severe disease.
3. Immune Evasion
Severe LASV infection is characterized by unchecked viremia, functional liver damage, and immunosuppression [29,30]. Viremia is strongly linked to disease manifestation and fatal outcomes. Viral evasion of immune mechanisms that would limit replication and spread would be beneficial to the virus. Inhibition of the antiviral state in infected cells as well as undiscovered infection by innate immune effector cells would allow efficient replication and dissemination. A lack of cytokine induction has been documented with pathogenic LASV and LCMV, strain WE [14,31,32]. In patients succumbing to LASV infection, the absence of IL-8 and IP-10, among a few other cytokines, was highly correlated to fatal outcome . Exposure of PBMC from healthy donors to LASV demonstrated that IFN-related and apoptotic genes, as well as NFκB and coagulation pathways were the most highly affected in gene expression analysis . However, treatment with IFN-I, but not IFN-γ, only limited arenavirus replication 10-fold in DC, and 10-100 fold in macrophages . In accordance with the minimal effect of IFN-I on viral replication, it has been well documented that the nucleoprotein of all arenaviruses, with the exception of Tacaribe (TACV), functions as an IFN-I antagonist [35,36,37]. It is possible that the regulation of IFN-I by NP provides for chronic infection of the virus in its natural host as both virulent and non-virulent arenaviruses antagonized IFN-I in a dose-dependent manner .
Additionally, arenaviruses have a specific tropism for APCs, in which they are able to infect without activating these cells [7,38,39]. In human DC:T-cell co-cultures, LASV induced only weak memory phenotype markers, while MOPV strongly stimulated CD8+ and CD4+ T cells, activation markers, proliferative responses, and cytotoxic lymphocyte (CTL) activities . We can speculate that TLR2-mediated production of cytokines in MOPV-infected cells  contributes to maturation of APC and thus strong adaptive immune responses. With 99% of the host cellular receptor, α-dystroglycan (DG), being expressed in the spleen, the virus is able to infect large numbers of APCs without initiating hallmark activation signals [34,39,40]. Infected DCs do not undergo migration or upregulation of costimulatory molecules thus allowing for efficient viral replication. These infected DCs may provide a reservoir of virus particles that can hide from immune surveillance. Infected macrophages lack phagocytic abilities and do not upregulate cytokines or chemokines that would recruit additional effector cells.
Collectively, the absence of cytokine production and the delayed maturation of APC potentially contributes to defective adaptive immune responses. The reduced expression of co-stimulatory molecules, CD40, CD80 and CD86, as well as down regulation of MHC class I and II molecules likely contributes to the observed lack of activated CD8+ and CD4+ T cells during infection in non-human primates and hence, an absence of cytotoxic function in mice [40,41,42,43,44]. However, while APCs fail to mature during arenavirus activation, they are still able to respond to external stimuli. Cytokines and costimulatory markers were upregulated even in infected cells when treated with LPS or poly:IC. Such treatment even inhibited viral replication, indicating that the cellular anti-viral mechanisms were not irreversibly damaged during infection .
Whether the inhibited induction of cytokines is a direct or indirect outcome of virulent virus infection, the lack of innate stimulation likely positions the host to have a delayed adaptive immune response that would effectively clear the infection. Suppression of cytokine responses, whether IFN-I or proinflammatory, might be necessary, but insufficient contributions to manifestation of disease. Pathogenesis may rely on other factors, such as viral replication, though replication of pathogenic and nonpathogenic strains was equivalent in vitro .
While a robust cell mediated immune response is observed ex vivo from patients surviving LASV infection, lack of efficient maturation of APCs and initiation of the adaptive CTL response may contribute to fatal LASV infections. Early responses to LASV infection are likely key to establishing a successful immune response. Given that IFN-I is poorly induced by LASV and that, with the exception of TACV, all arenaviruses encode an IFN-I antagonist, the proinflammatory immune response is likely necessary for establishing the ideal environment to combat arenavirus infection and limit viral replication. TLR2 is necessary for the proinflammatory response to LCMV in vitro and in vivo, however, the induction of proinflammatory responses by arenaviruses of different pathogenic potential has not been thoroughly examined.
5. Future Directions
Two important questions remain: how does TLR2 signaling contribute to resistance/recovery from arenavirus infection and how could the virus inhibit TLR2 signaling? To determine the importance of TLR2 signaling in protection against arenavirus infection, the correct animal model must be used. Mouse models of arenavirus infection rely on IFN-I rather than inflammatory cytokines and cytotoxic T cell responses. These mouse models provide more information for chronic infections rather than severe acute infections, such as those caused by LASV in humans. The non-human primate model most closely resembles the disease progression seen in humans. However, methods to decipher the contribution of TLR2 are more difficult to pursue in such models. The use of function-blocking antibody treatment may provide some insight. Studies could then be directed toward the activation of APC, T cells, or viral load, in the absence or reduction of TLR2 signaling. These types of studies could help elucidate the contribution of TLR2 signaling in the model presented below (Figure 3), in which pathogenic arenavirus fails to create an antiviral environment during the early stages of infection broadly affecting the ability to elicit an efficient adaptive immune response.
Along with the global effects of TLR2 signaling in arenavirus infection, it is still necessary to determine how arenaviruses stimulate the TLR2-dependent response and how this is inhibited during pathogenic arenavirus infection (Figure 4). We have demonstrated the requirement for live replicating virus and the differential activation of NFκB. From these results, we hypothesize that stimulation of TLR2 occurs during the replication cycle of the virus, whether via a viral component such as a protein-derived ligand or through viral RNA recognition. It is also possible that during the replicative cycle of the virus, the stress induced on the host cell results in release of danger signals that could then stimulate TLR2 . One possible method to determine the contribution of intracellular TLR2 signaling would be the use of intrabodies directed towards TLR2. Intrabodies are intracellular antibodies that are expressed and retained in the endoplasmic reticulum . Recently, an intrabody directed towards TLR2 was reported that was derived from a monoclonal antibody antagonistic to human and murine TLR2. This intrabody was able to retain TLR2 from the plasma membrane effectively and prevent NFκB activation from the cell surface. Additionally, the use of cross-linking studies and molecular imaging would also be useful in determining how arenaviruses are stimulating TLR2.
Ideally, one would like to singly express protein components of arenaviruses to determine if they stimulate TLR2. However, the requirement for live replicating virus confounds these efforts. The use of virus replicon particles (VRP) in which a replication defective virus particle encodes a gene under a separate promoter may help shed some light on this issue. VRPs could be used to express a particular gene of interest from either pathogenic or non-pathogenic arenaviruses. Additionally, using reverse genetics, proteins of pathogenic arenaviruses could be interchanged with the non-pathogenic protein, providing the replication necessary while singly expressing the pathogenic component.
By comparing the differences in TLR2-dependent responses during infection by arenaviruses of differing pathogenic potential for humans and non-human primates in vitro, we have provided a possible explanation for the development of severe disease in LASV infection. Further work in this area could entail looking for differences in TLR2 stimulation, TLR2 mutations, and TLR2-related SNPs to determine why some, but not all infected patients, succumb to LASV infection. Additionally, having identified the differences in TLR2-dependent cytokine responses between pathogenic and non-pathogenic virus infection, this work provides an avenue for development of therapeutics. With limited treatments available to use against LASV infection, use of TLR2 agonists may provide activation of the type of immune response necessary to clear virus more effectively and increase chances for survival. It is not clear whether activation of TLR2 signaling should be taken into account in vaccine design for arenaviruses. The ideal vaccine candidate for Old World arenaviruses would stimulate an efficient cytotoxic response and generate long lasting memory. Knowing the role of TLR2/Mal/MyD88 signaling in generating specific CD4+ and CD8+ T cell responses, and taking into consideration the inability of LASV to induce memory markers in T cells, it remains paradoxical that ML29, containing a small genomic segment from Lassa virus, has impaired induction of IL6 and IL8, yet is an excellent attenuated vaccine in non-human primates. Further reverse genetic and systems studies will be necessary to assess the role of the proinflammatory response in pathogenesis and protection.
Conflict of Interest
The authors declare no conflict of interest.
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