Background

Little is known about the neurocognitive outcome in children exposed to perinatal mother-to-child Chikungunya virus (p-CHIKV) infection.
Methods

The CHIMERE ambispective cohort study compared the neurocognitive function of 33 p-CHIKV-infected children (all but one enrolled retrospectively) at around two years of age with 135 uninfected peers (all enrolled prospectively). Psychomotor development was assessed using the revised Brunet-Lezine scale, examiners blinded to infectious status. Development quotients (DQ) with subscores covering movement/posture, coordination, language, sociability skills were calculated. Predictors of global neurodevelopmental delay (GND, DQ≤85), were investigated using multivariate Poisson regression modeling. Neuroradiologic follow-up using magnetic resonance imaging (MRI) scans was proposed for most of the children with severe forms.
Results

The mean DQ score was 86.3 (95%CI: 81.0–91.5) in infected children compared to 100.2 (95%CI: 98.0–102.5) in uninfected peers (P<0.001). Fifty-one percent (n = 17) of infected children had a GND compared to 15% (n = 21) of uninfected children (P<0.001). Specific neurocognitive delays in p-CHIKV-infected children were as follows: coordination and language (57%), sociability (36%), movement/posture (27%). After adjustment for maternal social situation, small for gestational age, and head circumference, p-CHIKV infection was found associated with GND (incidence rate ratio: 2.79, 95%CI: 1.45–5.34). Further adjustments on gestational age or breastfeeding did not change the independent effect of CHIKV infection on neurocognitive outcome. The mean DQ of p-CHIKV-infected children was lower in severe encephalopathic children than in non-severe children (77.6 versus 91.2, P<0.001). Of the 12 cases of CHIKV neonatal encephalopathy, five developed a microcephaly (head circumference <−2 standard deviations) and four matched the definition of cerebral palsy. MRI scans showed severe restrictions of white matter areas, predominant in the frontal lobes in these children.
Conclusions

The neurocognitive outcome of children exposed to perinatal mother-to-child CHIKV infection is poor. Severe CHIKV neonatal encephalopathy is associated with an even poorer outcome.

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Neurocognitive Outcome of Children Exposed to Perinatal Mother-to-Child Chikungunya Virus Infection: The CHIMERE Cohort Study on Reunion Island

National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency,Pathumthani, ThailandChikungunya virus (CHIKV) has recently re-emerged causing millions of infections in coun-tries around the Indian Ocean. While CHIKV hasa broad host cell range and productively infectsa number of different cell types, macrophageshave been identiﬁed as a potential viral reser-voir serving to increase the duration of symp-toms. To date no CHIKV interacting protein hasbeen characterized and this study sought toidentify CHIKV binding proteins expressed ontarget cell membranes. Two-dimensional virusoverlay identiﬁed prohibitin (PHB) as a micro-glial cell expressed CHIKV binding protein. Co-localization, co-immunoprecipitation as well asantibody and siRNA mediated infection inhibi-tion studies all conﬁrmed a role for PHB in me-diating internalization of CHIKV into microglialcells. PHB is the ﬁrst identiﬁed CHIKV receptorprotein, and this study is evidence that PHBmay play a role in the internalization of multipleviruses. J. Med. Virol. 84:1757–1770,2012.

Identification of prohibitin as a Chikungunya virus receptor protein

Organisms are constantly exposed to microbial pathogens in their environments. When a pathogen meets its host, a series of intricate intracellular interactions shape the outcome of the infection. The understanding of these host–pathogen interactions is crucial for the development of treatments and preventive measures against infectious diseases. Over the past decade, proteomic approaches have become prime contributors to the discovery and understanding of host–pathogen interactions that represent anti‐ and pro‐pathogenic cellular responses. Here, we review these proteomic methods and their application to studying viral and bacterial intracellular pathogens. We examine approaches for defining spatial and temporal host–pathogen protein interactions upon infection of a host cell. Further expanding the understanding of proteome organization during an infection, we discuss methods that characterize the regulation of host and pathogen proteomes through alterations in protein abundance, localization, and post‐translational modifications. Finally, we highlight bioinformatic tools available for analyzing such proteomic datasets, as well as novel strategies for integrating proteomics with other omic tools, such as genomics, transcriptomics, and metabolomics, to obtain a systems‐level understanding of infectious diseases.

Mol Syst Biol. (2017) 13: 922

https://www.embopress.org/doi/pdf/10.15252/msb.20167062

Proteomics and integrative omic approaches for understanding host–pathogen interactions and infectious diseases

Microglia, unique myeloid cells residing in the brain parenchyma, represent the first line of immune defense within the central nervous system In addition to their immune functions, microglial cells play an important role in other cerebral processes, including the regulation of synaptic architecture and neurogenesis Chronic microglial activation is regarded as detrimental, and it is considered a pathogenic mechanism common to several neurological disorders Microglial activation and function have been extensively studied in rodent experimental models, whereas the characterization of human cells has been limited due to the restricted availability of primary sources of human microglia To overcome this problem, human immortalized microglial cell lines have been developed The human microglial clone 3 cell line, HMC3, was established in 1995, through SV40-dependent immortalization of human embryonic microglial cells It has been recently authenticated by the American Type Culture Collection (ATCC®) and distributed under the name of HMC3 (ATCC®CRL-3304) The HMC3 cells have been used in six research studies, two of which also indicated by ATCC® as reference articles However, a more accurate literature revision suggests that clone 3 was initially distributed under the name of CHME3 In this regard, several studies have been published, thus contributing to a more extensive characterization of this cell line Remarkably, the same cell line has been used in different laboratories with other denominations, ie, CHME-5 cells and C13-NJ cells In view of the fact that “being now authenticated by ATCC®” may imply a wider distribution of the cells, we aimed at reviewing data obtained with the human microglia cell line clone 3, making the readers aware of this complicated nomenclature In addition, we also included original data, generated in our laboratory with the HMC3 (ATCC®CRL-3304) cells, providing information on the current state of the culture together with supplementary details on the culturing procedures to obtain and maintain viable cells

/pdf/the-human-microglial-hmc3-cell-line-where-do-we-stand-a-1jxxgn3jlq.pdf

The human microglial HMC3 cell line: where do we stand? A systematic literature review

The mammalian target of rapamycin (mTOR) is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors) and intracellular (energy status) molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs.

https://www.mdpi.com/1999-4915/8/6/152/pdf

Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway.

Chikungunya virus (CHIKV) is a recently re-emerged public health problem in many countries bordering the Indian Ocean and elsewhere. Chikungunya fever is a relatively self limiting febrile disease, but the consequences of chikungunya fever can include a long lasting, debilitating arthralgia, and occasional neurological involvement has been reported. Macrophages have been implicated as an important cell target of CHIKV with regards to both their role as an immune mediator, as well evidence pointing to long term viral persistence in these cells. Microglial cells are the resident brain macrophages, and so this study sought to define the proteomic changes in a human microglial cell line (CHME-5) in response to CHIKV infection. GeLC-MS/MS analysis of CHIKV infected and mock infected cells identified some 1455 individual proteins, of which 90 proteins, belonging to diverse cellular pathways, were significantly down regulated at a significance level of p<0.01. Analysis of the protein profile in response to infection did not support a global inhibition of either normal or IRES-mediated translation, but was consistent with the targeting of specific cellular pathways including those regulating innate antiviral mechanisms.

/pdf/proteomic-analysis-of-chikungunya-virus-infected-microgial-jvkdjo2qge.pdf

Bizunesh Abere

Papers

Proteomic analysis of chikungunya virus infected microgial cells.

Cell-type specific variation in the induction of ER stress and downstream events in chikungunya virus infection