Hantavirus Infection Suppresses Thrombospondin-1 Expression in Cultured Endothelial Cells in a Strain-Specific Manner.

Authors: Khaiboullina SF, Morzunov SP, St Jeor SC, Rizvanov AA, Lombardi VC.
Publication: Front Microbiol. 2016 Jul 19;7:1077. doi: 10.3389/fmicb.2016.01077. eCollection 2016.

Hantavirus infection is associated with two frequently fatal diseases in humans: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The pathogenesis of hantavirus infection is complex and not fully understood; however, it is believed to involve virus-induced hyperinflammatory immune responses. Thrombospondin-1 (THBS1) is a large homotrimeric protein that plays a putative role in regulating blood homeostasis. Hyperresponsiveness to inflammatory stimuli has also been associated with defects in the THBS1 gene. Our data suggest that hantavirus infection of human umbilical cord vein endothelial cells (HUVEC) suppress the accumulation of THBS1 in the extracellular matrix. Additionally, this suppression is dependent on virus replication, implying a direct mechanism of action. Our data also imply that the pathogenic Andes and Hantaan strains inhibit THBS1 expression while the non-pathogenic Prospect Hill strain showed little inhibition. These observations suggest that a dysregulation of THBS1 may contribute to the pathogenesis of hantavirus infection.

Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome

Authors: KA Schlauch1, SF Khaiboullina2,3, KL De Meirleir2, S Rawat2, J Petereit1, AA Rizvanov3, N Blatt3, T Mijatovic4, D Kulick5, A Palotás3,6 and
VC Lombardi1,2
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Publication: Citation: Transl Psychiatry (2015) 6, e●●; doi:10.1038/tp.2015.208

Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 9 06 600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge,
this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date.

Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-valueo0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene.

Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci. Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/ CFS, as well as categorize potential targets for medical intervention strategies.

Gut-Associated Plasmacytoid Dendritic Cells Display an Immature Phenotype and Upregulated Granzyme B in Subjects with HIV/AIDS

Authors: Sergei V. Boichuk,1,† Svetlana F. Khaiboullina,2,3,† Bulat R. Ramazanov,1 Gulshat R. Khasanova,1 Karina A. Ivanovskaya,4 Evgeny Z. Nizamutdinov, Marat R. Sharafutdinov, Ekaterina V. Martynova, Kenny L. DeMeirleir, Jan Hulstaert, Vladimir A. Anokhin, Albert A. Rizvanov, and Vincent C. Lombardi
Publication: Frontiers in Immunology
Front Immunol. 2015; 6: 485.
Published online 2015 Sep 24. doi: 10.3389/fimmu.2015.00485

Plasmacytoid dendritic cells (pDCs) in the periphery of subjects with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) decrease over time, and the fate of these cells has been the subject of ongoing investigation. Previous studies using animal models as well as studies with humans suggest that these cells may redistribute to the gut. Other studies using animal models propose that the periphery pDCs are depleted and gut is repopulated with naive pDCs from the bone marrow. In the present study, we utilized immunohistochemistry to survey duodenum biopsies of subjects with HIV/AIDS and controls. We observed that subjects with HIV/AIDS had increased infiltration of Ki-67+/CD303+ pDCs, a phenotype consistent with bone marrow-derived pre-pDCs. In contrast, Ki-67+/CD303+ pDCs were not observed in control biopsies. We additionally observed that gut-associated pDCs in HIV/AIDS cases upregulate the proapoptotic enzyme granzyme B; however, no granzyme B was observed in the pDCs of control biopsies. Our data are consistent with reports in animal models that suggest periphery pDCs are depleted by exhaustion and that naive pDCs egress from the bone marrow and ultimately infiltrate the gut mucosa. Additionally, our observation of granzyme B upregulation in naive pDCs may identify a contributing factor to the gut pathology associated with HIV infection.

Multiplex Analysis of Serum Cytokines in Humans with Hantavirus Pulmonary Syndrome.

Authors: Morzunov SP, KhaiboullinSF, St Jeor S, Rizvanov AA, Lombardi VC.
Publication: Frontiers in Immunology Front Immunol. 2015 Aug 31;6:432. doi: 10.3389/fimmu.2015.00432. eCollection 2015.

Hantavirus pulmonary syndrome (HPS) is an acute zoonotic disease transmitted primarily through inhalation of virus-contaminated aerosols. Hantavirus infection of endothelial cells leads to increased vascular permeability without a visible cytopathic effect. For this reason, it has been suggested that the pathogenesis of HPS is indirect with immune responses, such as cytokine production, playing a dominant role. In order to investigate their potential contribution to HPS pathogenesis, we analyzed the serum of hantavirus-infected subjects and healthy controls for 68 different cytokines, chemokines, angiogenic, and growth factors. Our analysis identified differential expression of cytokines that promote tissue migration of mononuclear cells including T lymphocytes, natural killer cells, and dendritic cells. Additionally, we observed a significant upregulation of cytokines known to regulate leukocyte migration and subsequent repair of lung tissue, as well as cytokines known to increase endothelial monolayer permeability and facilitate leukocyte transendothelial migration. Conversely, we observed a downregulation of cytokines associated with platelet numbers and function, consistent with the thrombocytopenia observed in subjects with HPS. This study corroborates clinical findings and extends our current knowledge regarding immunological and laboratory findings in subjects with HPS.

Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis.

Khaiboullina SF, DeMeirleir KL, Rawat S, Berk GS, Gaynor-Berk RS, Mijatovic T, Blatt N, Rizvanov AA, Young SG, Lombardi VC.
Publication: Cytokine. 2015 Mar;72(1):1-8. doi: 10.1016/j.cyto.2014.11.019. Epub 2014 Dec 13.

Gulf War illness (GWI) is a chronic disease of unknown etiology characterized by persistent symptoms such as cognitive impairment, unexplained fatigue, pervasive pain, headaches, and gastrointestinal abnormalities. Current reports suggest that as many as 200,000 veterans who served in the 1990-1991 Persian Gulf War were afflicted. Several potential triggers of GWI have been proposed including chemical exposure, toxins, vaccines, and unknown infectious agents. However, a definitive cause of GWI has not been identified and a specific biological marker that can consistently delineate the disease has not been defined. Myalgic encephalomyelitis (ME) is a disease with similar and overlapping symptomology, and subjects diagnosed with GWI typically fit the diagnostic criteria for ME. For these reasons, GWI is often considered a subgroup of ME. To explore this possibility and identify immune parameters that may help to understand GWI pathophysiology, we measured 77 serum cytokines in subjects with GWI and compared these data to that of subjects with ME as well as healthy controls. Our analysis identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-α, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters. These results imply that serum cytokines are representative of ME pathology to a greater extent than GWI and further suggest that the two diseases have distinct immune profiles despite their overlapping symptomology.

Plasmacytoid dendritic cells, a role in neoplastic prevention and progression.

Authors: Lombardi VC, Khaiboullina SF, Rizvanov AA.
Publication: Eur J Clin Invest. 2015 Jan;45 Suppl 1:1-8. doi: 10.1111/eci.12363.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) are multifunctional bone-marrow-derived immune cells that are key players in bridging the innate and adaptive immune systems. Activation of pDCs through toll-like receptor agonists has proven to be an effective treatment for some neoplastic disorders.
MATERIALS AND METHODS: In this mini-review, we will explore the fascinating contribution of pDCs to neoplastic pathology and discuss their potential utilization in cancer immunotherapy.
RESULTS: Current research suggests that pDCs have cytotoxic potential and can effectively induce apoptosis of tumour-derived cells lines. They are also reported to display tolerogenic function with the ability to suppress T-cell proliferation, analogous to regulatory T cells. In this capacity, they are critical in the suppression of autoimmunity but can be exploited by tumour cells to circumvent the expansion of tumour-specific T cells, thereby allowing tumours to persist.
CONCLUSION: Several forms of skin cancer are successfully treated with the topical drug Imiquimod, which activates pDCs through toll-like receptor 7 engagement. Additionally, pDC-based anticancer vaccines have shown encouraging results for the treatment of melanoma in early trials. Future studies regarding the contributions of pDCs to malignancy will likely afford many opportunities for immunotherapy strategies.