Biology And Pathogenesis Of Chikungunya Virus Pdf

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The virus is spread between people by two types of mosquitos : Aedes albopictus and Aedes aegypti. The best means of prevention is overall mosquito control and the avoidance of bites in areas where the disease is common.

Chikungunya is a severe and debilitating disease. Currently, Brazil is experiencing an epidemic caused by three arboviruses, which has changed the way health professionals have diagnosed and treated infected patients. The difficulty of diagnosis and the lack of a protocol for patient treatment, which fits Brazilian health system models, have made it difficult to manage this disease. It is necessary to implement a multidisciplinary network of patient care, in which primary care units play the main role. This review aims to present current information regarding the clinical aspects and treatment of Chikungunya virus infection.


In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis.

Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation. The observations provided valuable insights into virus-host interactions during the acute phase and can be instrumental in the investigation of new and effective therapeutic interventions.

These dramatic effects call for a careful evaluation of the molecular mechanisms involved in this puzzling infection. By analyzing the blood transcriptome of adults acutely infected with CHIKV, we were able to provide a detailed picture of the early molecular events induced by the infection. Additionally, the systems biology approach revealed genes that can be investigated extensively as probable therapeutic targets for the disease.

PLoS Pathog 15 6 : e This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: H. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist. The Chikungunya virus CHIKV is a mosquito-borne reemerging arbovirus responsible for intermittent and devastating outbreaks [ 1 ].

The disease has afflicted four continents, affected more than countries and infected over 10 million people [ 2 , 3 ]. Its global impact is still growing [ 4 ]. CHIKV has spread rapidly through several Brazilian states and infected a total of 20, individuals in [ 5 ]; furthermore, more than , suspected cases were reported in — [ 6 ]. Mortality rates are estimated to be approximately 0. Several studies have sought to understand the CHIKV disease pathogenesis and virus-host interactions better [ 12 ] using in vitro approaches [ 13 ] or animal models [ 14 , 15 ].

Systems biology approaches have been successfully applied to identify molecular signatures associated with infections [ 16 ] and vaccination [ 17 ]. In this study, a systems approach was performed to investigate subjects who were naturally infected with CHIKV during the epidemics in the state of Sergipe, Brazil.

Eight patients reported having had symptoms for two days, and seven reported symptoms surfacing three to four days prior to the blood collection.

Two patients reported pain for the past 20 days or more Fig 1a. The status of long-term arthralgia was assessed in some of the patients and indicated by the following color scheme: chronic orange , non-chronic green and undetermined gray.

Blood was also collected from 20 healthy subjects from endemic and non-endemic regions in Brazil. Although the CHIKV RNA levels had a small contribution to the variance observed in the transcriptomes, individuals were not grouped by the days post the onset of symptoms or by their infection status i. SERPING1 C1 inhibitor is a novel finding since this inhibitor of the classical pathway of the complement system has not been associated with arthritogenicalphaviruses [ 23 ], although it is up-regulated in monocytes in HIV infections [ 24 ].

The stars correspond with the gene sets used to construct the networks shown in panel C negatively correlated pathways and S2 Fig positively correlated pathways.

The gray nodes were added by NetworkAnalyst and are not a part of the correlated genes. The expression of several eukaryotic translation initiation factors eIFs was negatively correlated with the level of CHIKV RNA Fig 3 , indicating that these genes can play a major role in viral replication.

The eIFs are important proteins for controlling the translation initiation processes involved in host and viral protein syntheses [ 25 ]. This protein is activated by alphavirus infections and contributes to the characteristic shut-down of host cell protein synthesis, thereby allowing the preferential translation of capped viral RNA [ 26 ].

Due to the natural heterogeneity in human cohorts, we also performed differential expression analyses between each infected patient and the group of healthy controls. The DEG list for each patient was subsequently combined into a meta-volcano plot Fig 4b. This plot displays the number of genes whose expression was consistently altered in most patients. APOBEC3 family members are important cytidine deaminases that control inter alia HIV replication [ 27 ] but have, to the best of our knowledge, not previously been associated with alphaviral infections.

The colors represent the number of up-regulated red or down-regulated blue genes and the respective number of genes in each group.

The x-axis represents the number of consistent differential expressions of each gene while the y-axis represents the number of studies in which the genes were classified as a DEG. Chemotherapeutic inhibition of the NLRP3 inflammasome was recently shown to inhibit CHIKV arthropathy in a mouse model [ 30 ]; the current study, therefore, confirms this pathway as a potential drug target in humans.

Nlrp3 is transcriptionally regulated to guarantee high protein levels for the activation of the NLRP3 inflammasome. Taken together, our results expand the knowledge available about host-CHIKV interaction and provide potential therapeutic strategies that target the NLRP3 inflammasome [ 32 ].

The random forest method, a machine learning approach, was also employed to rank the importance of the DEGs mentioned in the meta-volcano analysis Fig 4b in predicting the CHIKV infection status. S3 Fig displays the 38 genes that better distinguish between the infected patients and healthy control samples from feature selection interactions S3a Fig. The lectin pathway has been implicated as causing the tissue damage during alphaviral arthritis caused by the Ross River virus [ 23 ], and SerpinG1 upregulation may act to limit such damage [ 34 ].

We next performed single sample GSEA analysis using the log2 fold-change values of each patient compared to the group of healthy controls as ranks and the BTMs as gene sets S4 Fig. Similar to the results presented in Fig 2 , we observed that the up-regulated BTMs were related to innate immunity and antiviral responses involving dendritic cells and monocytes activation. This is highly consistent with the work of Michlmayr et al [ 35 ].

Compared to the healthy controls, a total of 1, and 1, genes were consistently differentially expressed in most of the chronic and non-chronic patients respectively S5b Fig. Of them, genes were commonly up-regulated and were down-regulated in both groups S5c Fig. Additionally, a high positive correlation was observed between the mean log2 fold change of chronic and non-chronic patients when compared to healthy controls S5d Fig.

However, few genes presented an expression profile that differed between chronic and non-chronic patients S5d Fig. However, such changes may merely be associated with the diminishing of the acute adaptive T cell responses [ 22 ].

Of considerably greater interest are the genes that are up-regulated in most chronic patients relative to non-chronic patients. However, our analyses might simply be a reflection of a greater number of males in the chronic group since several of the genes identified were Y linked.

This analysis, thus, provides no support for the notion of the onset of new pathological processes in chronic diseases—an observation in agreement with murine studies [ 22 ].

We performed a gene co-expression network analysis using the expression profiles of all the patients and healthy controls. CEMiTool [ 37 ] identified eight co-expression modules containing 74 to over 2, genes Fig 5a.

The expression activity of some of these modules were altered in healthy controls or in patients that had different days post the onset of symptoms Fig 5b. Module M8, which shows higher activity in patients with two to four days of symptoms was enriched for monocytes and neutrophils Fig 5c.

A monocyte centric response in peripheral blood from pediatric CHIKV patients has previously been documented [ 35 ] and a protective role was observed in murine models [ 22 ]. Nevertheless, although previously thought to characterize bacterial infections, neutrophil responses are now recognized in a range of acute viral infections [ 40 , 41 ].

The colors of rectangles represent the days post the onset of symptoms, and the black line represents the mean expression of all the genes inside the module. The size and color of the circles represent the normalized enrichment score NES. The pathways were ordered by significance as indicated on the x-axis. The size of the node represents its degree of connectivity. Another gene identified is AIM2 Fig 5d , an interferon-inducible cytoplasmic dsDNA sensor that activates the inflammasome and triggers pyroptosis.

We re-analyzed two publicly available blood transcriptome datasets and identified the genes whose expression was altered in the Dengue infected patients and RA patients compared to healthy controls. The size of the bar represents the quantity of up-regulated genes detected in one or more groups indicated as a gray circle in the graph below. Representative up-regulated genes are displayed.

The gray circles below the bars indicate the groups that share the same up-regulated genes. Since the inflammasome-related genes are exclusively up-regulated in CHIKV infection and were described before in this context [ 30 ], we decided to provide a deeper proof-of-concept related to these findings.

The murine bone marrow-derived macrophages were infected with CHIKV virus and the readouts of the inflammasome activation were measured. These data support the view that the inflammasome is activated in response to CHIKV infection and are consistent with our transcriptional analyses [and murine studies [ 30 ]]. The percentage left and the integrated mean of fluorescence iMFI of the activated cells right is shown. Asterisks indicate statistically significant differences. CHIKV re-emergence in the past 15 years has led to major epidemic outbreaks in Asia, Africa, the Indian Ocean and more recently in the Americas after decades of intermittent outbreaks [ 48 ].

Despite considerable progress in understanding the infection, much of the host-pathogen interplay remains obscure. Systems biological approaches can provide comprehensive and unbiased dissections of the complex interactions between genes and proteins in infections [ 16 ]. However, these were restricted to the analysis of a limited number of proteins [ 49 ] or of children infected with the virus [ 50 ]. Since it is extremely difficult to acquire sufficient data from naturally infected individuals for use in systems biological models of analysis, this kind of study is relatively new.

The aim of the present study was to investigate the early host response to acute CHIKV infection in adults using a systems biological approach. We acknowledge that our cohort is a limited representation of the Brazilian population. The most clinically relevant symptom related to CHIKV infection is peripheral symmetrical joint pain primarily inflammatory polyarthralgia. Since there are neither effective treatments nor licensed vaccines against CHIKV infection, understanding the molecular mechanisms of this complex infection is essential for the development of effective therapies and even vaccines.

Thus, we believe that in Brazilian regions with different CHIKV strains, the virulence and pathogenesis of the disease may vary. Consistent with other reports, it was observed that the up-regulation of several genes play a role in the antiviral immune response, and many of them are ISGs [ 15 , 56 , 57 ].

Similarly, other reports that assessed the changes in immune cell subsets during CHIKV infection [ 50 , 58 ] support the findings of this study regarding the most abundant up-regulated genes being related to neutrophils and myeloid populations and especially dendritic cells and monocytes. The monocytes have been reported recently as important inflammatory and regulatory mediators of the innate immune response to different arboviruses [ 16 , 59 ].

Corroborating with these findings, the exclusive up-regulation of inflammasome-related genes was also observed. Additionally, the induction of inflammasome activation in macrophages infected with CHIKV in vitro was observed.

In our previous work, we and others showed that the CHIKV infection in wild type mice induced important musculoskeletal diseases and proved it to be an appropriate murine model to study human pathogenesis [ 30 , 60 ].

Furthermore, it is speculated whether the down-regulation of other eIF family members observed in these results in response to the infection could be an important host defense mechanism against the virus replication.

Moreover, the protein levels may differ from the gene RNA levels detected in this work. We consider the eukaryotic translation initiation factors as potential markers of the CHIKV arthralgia chronicity and can be better exploited as novel broad-spectrum antiviral targets.

The CHIKV-related arthralgia symptom is significantly similar to rheumatoid arthritis RA but there are some important clinical and immunological characteristics that differ between these diseases and the different molecular signatures between both CHIKV and RA can be indicated here.

Here, we are presenting a more detailed comparison between both diseases in humans. It is well known that the CHIKV-related polyarthralgia affects joints and presents high inflammatory mediators that release locally as a result of the infiltration of mononuclear cells [ 48 , 60 ]. Therefore, a study comparing the macrophage transcriptome in synovial fluid of both RA and CHIKV infection patients would be highly informative and enriching. Contrariwise, when compared to the differential gene expressions of DENV infected patients, the data in this study shows specific molecular gene signatures in response to CHIKV.

Chikungunya Virus

Host-pathogen interactions during arboviral infections View all 13 Articles. Chikungunya virus CHIKV is a re-emergent arthropod-borne virus arbovirus that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia. In the last decade, CHIKV has become a serious public health problem causing several outbreaks around the world. Despite the fact that CHIKV has been around since , our knowledge about immunopathology, innate and adaptive immune response involved in this infectious disease is incomplete. In this review, we provide an updated summary of the current knowledge about immune response to CHIKV and about soluble immunological markers associated with the morbidity, prognosis and chronicity of this arbovirus disease. In addition, we discuss the progress in the research of new vaccines for preventing CHIKV infection and the use of monoclonal antibodies as a promising therapeutic strategy.

It seems that you're in Germany. We have a dedicated site for Germany. This book describes the molecular biology, pathogenesis, epidemiology, and potential strategies for control of chikungunya virus CHIKV infection. It offers insight into the structure and functions of CHIKV proteins as they relate to host response, interaction with the arthropod vector, and vaccination. A detailed account of both the epidemiological outlook and the clinical syndrome of CHIKV infection is provided.

Cellular and Molecular Immune Response to Chikungunya Virus Infection

In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation.

Key Points

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