**10. Immune-pathogenesis**

Given the expanding geographic range of CHIKV and its potential to rapidly cause large scale epidemics, it has become important to understand the immune and pathogenic mechanisms active during CHIKV infections in order to guide the development of targeted and effective control and treatment strategies.

In a review the possible interactions of the immune system with the different stages of the CHIKV life cycle have been discussed (Kam et al., 2009). The first encounter of CHIKV with human host is intradermal inoculation by the mosquito: replication of the virus starts at the site of inoculation. Different resident cell types are present in this location, including keratinocytes, dermal dendritic cells (DCs), Langerhans cells (LCs), and dermal macrophages, cells involved in the innate immune response.

The innate immune response is the first barrier against viruses, being able to inhibit viral replication through cytolytic and non-cytolytic mechanisms. IFN system plays an important role in limiting virus spread at an early stage of infection. *In vitro* growth of all tested alphaviruses can be greatly suppressed by the antiviral effects of Interferon-/IFN when it is added to cells prior to infection, and, more specifically, CHIKV replication is significantly influenced by type I and II IFNs (Courderc et al., 2008; Schilte et al., 2010; Sourisseau et al., 2007). The finding that aberrant Type I interferon signalling in mice led to severe forms of CHIKF (Couderc et al., 2008) further highlighted important roles cytokines play in the pathology of CHIKV infection. Moreover, in a very recent study Wauquier and colleague demonstrated that CHIKV infection in humans elicit strong innate immunity involving the production of numerous proinflammatory mediators. Interestingly, high levels of Interferon IFN-α were consistently found. Production of interleukin (IL) 4, IL-10, and IFN-γ suggested the engagement of the adaptive immunity. This was confirmed by flow cytometry of circulating T lymphocytes that showed a CD8+ T lymphocyte response in the early stages of the disease, and a CD4+ T lymphocyte mediated response in the later stages (Wauquier et al., 2011).

It was already known that skin cell fibroblasts were susceptible to CHIKV infection (Sourisseau et al.,2007); recently has also been demonstrated that CHIKV antigens could be detected *in vivo* in the monocytes of acutely infected patients (Her et al, 2010). CHIKV

the Indian Ocean outbreak (M269V and D284E). Concerning the A226V mutation, this was present in all imported and autochthonous cases, with the exception of the isolate imported from the Indian subcontinent in 2006. The absence of this mutation in the isolate imported in 2006 from India was in agreement with published data (Arankalle et al., 2007), and with available GenBank sequence data, indicating that the virus strains circulating in India in

The presence of A226V in the isolate imported from India in July 2007 and in the isolates from the 2007 Italian outbreak (originating from a case imported from India) supports the view that the virus envelope sequence of strains from India changed over time, acquiring after 2006 the E1 mutation associated with enhanced fitness in *Aedes albopictus*. So it appears that the acquisition and fixation of the A226V mutation may be a common pathway of chikungunya explosion in epidemic areas, in a parallel interplay with the mosquito vector dynamics. Noteworthy, the outbreak in Singapore, where the A226V mutation was absent,

Given the expanding geographic range of CHIKV and its potential to rapidly cause large scale epidemics, it has become important to understand the immune and pathogenic mechanisms active during CHIKV infections in order to guide the development of targeted

In a review the possible interactions of the immune system with the different stages of the CHIKV life cycle have been discussed (Kam et al., 2009). The first encounter of CHIKV with human host is intradermal inoculation by the mosquito: replication of the virus starts at the site of inoculation. Different resident cell types are present in this location, including keratinocytes, dermal dendritic cells (DCs), Langerhans cells (LCs), and dermal

The innate immune response is the first barrier against viruses, being able to inhibit viral replication through cytolytic and non-cytolytic mechanisms. IFN system plays an important role in limiting virus spread at an early stage of infection. *In vitro* growth of all tested alphaviruses can be greatly suppressed by the antiviral effects of Interferon-/IFN when it is added to cells prior to infection, and, more specifically, CHIKV replication is significantly influenced by type I and II IFNs (Courderc et al., 2008; Schilte et al., 2010; Sourisseau et al., 2007). The finding that aberrant Type I interferon signalling in mice led to severe forms of CHIKF (Couderc et al., 2008) further highlighted important roles cytokines play in the pathology of CHIKV infection. Moreover, in a very recent study Wauquier and colleague demonstrated that CHIKV infection in humans elicit strong innate immunity involving the production of numerous proinflammatory mediators. Interestingly, high levels of Interferon IFN-α were consistently found. Production of interleukin (IL) 4, IL-10, and IFN-γ suggested the engagement of the adaptive immunity. This was confirmed by flow cytometry of circulating T lymphocytes that showed a CD8+ T lymphocyte response in the early stages of the disease, and a CD4+ T lymphocyte mediated response in the later

It was already known that skin cell fibroblasts were susceptible to CHIKV infection (Sourisseau et al.,2007); recently has also been demonstrated that CHIKV antigens could be detected *in vivo* in the monocytes of acutely infected patients (Her et al, 2010). CHIKV

2006 lacked this mutation.

has been rapidly controlled.

**10. Immune-pathogenesis** 

stages (Wauquier et al., 2011).

and effective control and treatment strategies.

macrophages, cells involved in the innate immune response.

interactions with monocytes, and with other blood leukocytes, induced a robust and rapid innate immune response with the production of specific chemokines and cytokines. In particular, high levels of IFN-were rapidly produced after CHIKV incubation with monocytes. The identification of monocytes during the early phase of CHIKV infection *in vivo* is significant as infected monocyte/macrophage cells have been detected in the synovial tissues of chronically CHIKV-infected patients, and these cells may behave as the vehicles for virus dissemination. This may explain the persistence of joint symptoms despite the short duration of viraemia (Her et al., 2010).

Since the A226V mutation has been associated with enhanced replication and fitness of CHIKV in *A. albopictus* vector and has also been shown to modulate cholesterol requirement for infection of insect cells (Tsetsarkin et al*.*, 2007), in a recent paper we investigated the possible involvement of A226V mutation in enhancing human pathogenesis in non vector hosts, by testing the replication competence in primate cell cultures of two isolates, differing for the presence or absence of this mutation (Bordi et al., 2011). We observed that the presence of A226V mutation did not influence the replication kinetics on primate cells. Moreover, the time course of appearance of cytopathic effect (CPE) and of cells immunostained with CHIKV-specific antiserum, was very similar for both the isolates, as well as the shape of the virus-positive multicellular foci, thus suggesting a similar mechanism of spread of the virus in the infected cell cultures.

In addition, we considered the possibility that the A226V mutation could be associated with partial resistance to the inhibitory action of IFN- in classical experiments of inhibition of virus replication. Surprisingly, the A226V-carrying strain was more susceptible to the antiviral action of recombinant IFN-. (Fig.3)

Fig. 3. Dose-dependent reduction of viral CPE by recombinant IFN-.

*In vitro* experiments of inhibition of virus replication by recombinant IFN- on Vero E6 cells showing a dose-dependent reduction of CPE for both isolates: the A226V, carrying isolate and the wt (Bordi et al., New Microbiol, 2011).

The Re-Emergence of an Old Disease: Chikungunya Fever 131

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Overall, our result did not support the concept that A226V mutation confers a replicative advantage in primate cell cultures, neither supported the possibility that partial resistance to the inhibitory action of IFN- could account for the explosive spread of the mutated strain in the human population in the countries where this mutation had occurred. However, the possibility that the interplay between the virus and the innate defence system may act at different levels of the virus/host interaction is to be taken into consideration, by exploring, for instance, other steps of the IFN response activation.

At the moment, understanding CHIKV immuno-biology is still in its infancy and there is a long way to go before answers related to the interaction between virus and host immunity will be obtained. These will certainly be important in designing novel antiviral control strategies against the spread of CHIKV infection.

#### **11. References**


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**Part 2** 

**and Helminths** 

**Tropical Diseases Due to Protozoa** 

