Pseudomonas aeruginosa Stimulates Inflammation and Enhances Kaposi's Sarcoma Herpesvirus-Induced Cell Proliferation and Cellular Transformation through both Lipopolysaccharide and Flagellin.

Inflammation triggered by innate immunity promotes carcinogenesis in cancer. Kaposi's sarcoma (KS), a hyperproliferative and inflammatory tumor caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection, is the most common cancer in AIDS patients. KSHV infection sensitizes cells to pathogen-associated molecular patterns (PAMPs). We examined the role of Pseudomonas aeruginosa, an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. P. aeruginosa stimulation increased cell proliferation and efficiency of colony formation in soft agar of KSHV-transformed rat primary mesenchymal precursor (KMM) cells but had no significant effect on the untransformed (MM) cells. P. aeruginosa stimulation also increased cell proliferation of KSHV-infected human B cells, BJAB, but not the uninfected cells. Mechanistically, P. aeruginosa stimulation resulted in increased inflammatory cytokines and activation of p38, ERK1/2, and JNK mitogen-activated protein kinase (MAPK) pathways in KMM cells while having no obvious effect on MM cells. P. aeruginosa induction of inflammation and MAPKs was observed with and without inhibition of the Toll-like receptor 4 (TLR4) pathway, while a flagellin-deleted mutant of P. aeruginosa required a functional TLR4 pathway to induce inflammation and MAPKs. Furthermore, treatment with either lipopolysaccharide (LPS) or flagellin alone was sufficient to induce inflammatory cytokines, activate MAPKs, and increase cell proliferation and efficiency of colony formation in soft agar of KMM cells. These results demonstrate that both LPS and flagellin are PAMPs that contribute to P. aeruginosa induction of inflammation in KSHV-transformed cells. Because AIDS-KS patients are susceptible to P. aeruginosa infection, our work highlights the preventive and therapeutic potential of targeting P. aeruginosa infection in these patients.IMPORTANCE Kaposi's sarcoma (KS), caused by infection with Kaposi's sarcoma-associated herpesvirus (KSHV), is one of the most common cancers in AIDS patients. KS is a highly inflammatory tumor, but how KSHV infection induces inflammation remains unclear. We have previously shown that KSHV infection upregulates Toll-like receptor 4 (TLR4), sensitizing cells to lipopolysaccharide (LPS) and Escherichia coli In the current study, we examined the role of Pseudomonas aeruginosa, an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. P. aeruginosa stimulation increased cell proliferation, inflammatory cytokines, and activation of growth and survival pathways in KSHV-transformed cells through two pathogen-associated molecular patterns, LPS and flagellin. Because AIDS-KS patients are susceptible to P. aeruginosa infection, our work highlights the preventive and therapeutic potential of targeting P. aeruginosa infection in these patients.

Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway.

Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.

Kaposi Sarcoma-Associated Herpesvirus Infection and Endemic Burkitt Lymphoma.

BACKGROUND: Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria coinfections. However, the role of Kaposi sarcoma-associated herpesvirus (KSHV), also endemic in Africa, has not been evaluated as a cofactor in eBL pathogenesis. METHODS: Multiplexed seroprofiles for EBV, malaria, and KSHV were generated for 266 eBL patients, 78 non-eBL cancers, and 202 healthy children. KSHV and EBV loads were quantified by PCR. RESULTS: KSHV seroprevalence did not differ by study group but was associated with age. Seropositivity, defined by K8.1/LANA or in combination with 5 other KSHV antigens (ORF59, ORF65, ORF61, ORF38, and K5) was associated with antimalarial antibody levels to AMA1 (odds ratio [OR], 2.41, P < .001; OR, 2.07, P < .001) and MSP1 (OR, 2.41, P = .0006; OR, 5.78, P < .001), respectively. KSHV loads did not correlate with antibody levels nor differ across groups but were significantly lower in children with detectable EBV viremia (P = .014). CONCLUSIONS: Although KSHV-EBV dual infection does not increase eBL risk, EBV appears to suppress reactivation of KSHV while malaria exposure is associated with KSHV infection and/or reactivation. Both EBV and malaria should, therefore, be considered as potential effect modifiers for KSHV-associated cancers in sub-Saharan Africa.

Rare presentation of bronchopulmonary Kaposi sarcoma.

Kaposi sarcoma (KS) is an angioproliferative disorder that is commonly associated with human herpes virus 8 as well as the HIV. In fact, KS is one of the most common AIDS-defining illnesses. KS typically presents with diffuse, violaceous cutaneous nodules, and may have concomitant visceral involvement. However, visceral involvement rarely occurs without skin manifestations. A rare case of localised bronchopulmonary KS without skin involvement is described in a patient with previously undiagnosed HIV. This atypical presentation represents a challenge for modern-day physicians in developed countries where the prevalence of AIDS-related diseases is decreasing.

¿Cómo tratamos el hemangioendotelioma kaposiforme? / How do we treat Kaposiform Haemangioendothelioma?

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Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Associated Disease in the AIDS Patient: An Update.

In this book chapter, we review the current knowledge of the biology and pathogenesis of Kaposi's sarcomaassociated herpesvirus (KSHV). We describe the lifecycle of KSHV, the cancers associated with this virus, as well as current treatment modalities.

Signal Transduction Pathways Associated with KSHV-Related Tumors.

Signal transduction pathways play a key role in the regulation of cell growth, cell differentiation, cell survival, apoptosis, and immune responses. Bacterial and viral pathogens utilize the cell signal pathways by encoding their own proteins or noncoding RNAs to serve their survival and replication in infected cells. Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is classified as a rhadinovirus in the γ-herpesvirus subfamily and was the eighth human herpesvirus to be discovered from Kaposi's sarcoma specimens. KSHV is closely associated with an endothelial cell malignancy, Kaposi's sarcoma, and B-cell malignancies, primary effusion lymphoma, and multicentric Castleman's disease. Recent studies have revealed that KSHV manipulates the cellular signaling pathways to achieve persistent infection, viral replication, cell proliferation, anti-apoptosis, and evasion of immune surveillance in infected cells. This chapter summarizes recent developments in our understanding of the molecular mechanisms used by KSHV to interact with the cell signaling machinery.

Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Replications.

Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and nontreatable malignancy commonly found in AIDS patients. In this study, we performed a high-throughput screening of 3,731 characterized compounds and identified cytarabine, approved by the FDA for treating numerous types of cancer, as a potent inhibitor of KSHV-induced PEL. We showed the high efficacy of cytarabine in the growth inhibition of various PEL cells by inducing cell cycle arrest and apoptosis. Cytarabine inhibited host DNA and RNA syntheses and therefore induced cellular cytotoxicity. Furthermore, cytarabine inhibited viral DNA and RNA syntheses and induced the rapid degradation of KSHV major latent protein LANA (latency-associated nuclear antigen), leading to the suppression of KSHV latent replication. Importantly, cytarabine effectively inhibited active KSHV replication and virion production in PEL cells. Finally, cytarabine treatments not only effectively inhibited the initiation and progression of PEL tumors but also induced regression of grown PEL tumors in a xenograft mouse model. Altogether, our study has identified cytarabine as a novel therapeutic agent for treating PEL as well as eliminating KSHV persistent infection.IMPORTANCE Primary effusion lymphoma is an aggressive malignancy caused by Kaposi's sarcoma-associated herpesvirus. The outcome of primary effusion lymphoma is dismal without specific treatment. Through a high-throughput screening of characterized compounds, we identified an FDA-approved compound, cytarabine, as a potent inhibitor of primary effusion lymphoma. We showed that cytarabine induced regression of PEL tumors in a xenograft mouse model. Cytarabine inhibited host and viral DNA and RNA syntheses, resulting in the induction of cytotoxicity. Of interest, cytarabine induced the degradation of KSHV major latent protein LANA, hence suppressing KSHV latent replication, which is required for PEL cell survival. Furthermore, cytarabine inhibited KSHV lytic replication program, preventing virion production. Our findings identified cytarabine as a novel therapeutic agent for treating PEL as well as for eliminating KSHV persistent infection. Since cytarabine is already approved by the FDA, it might be an ideal candidate for repurposing for PEL therapy and for further evaluation in advanced clinical trials.

Recommendations for Counseling and Education of Service Members on Endemic African Cutaneous Kaposi Sarcoma: A Case Study.

We report a case of Endemic African Cutaneous Kaposi Sarcoma (EACKS) on the lower extremity of an immunocompetent 31-yr-old male service member from Cameroon. Diagnosis was made using clinical and histologic findings. The service member was treated with local radiation therapy with resolution of his tumor.The goal of this article is to educate practitioners to counsel susceptible service members and leadership on the risk of developing EACKS when traveling to Sub-Saharan Africa, monitor for disease development, and guide in the diagnosis and treatment of patients with this rare disease.

Restricted Range of Motion and a Cold Upper Extremity in a Two-Year-Old Boy: Kaposiform Hemangioendothelioma of the Bone and the Brachial Plexus: A Case Report.

CASE: We report a case of kaposiform hemangioendothelioma (KHE) of the scapula in a 2-year-old boy with motor and sensory abnormalities of the left upper extremity, suggesting brachial plexus involvement. The locally invasive nature prevented resection; sirolimus therapy resulted in improvement of the motor and sensory impairment, as well as decreased tumor size on imaging. CONCLUSION: Osseous infiltration of KHE is known to occur, but its primary presentation in bone without skin involvement is rare and diagnostically challenging. Awareness of rare presentations of KHE, along with accurate histopathologic interpretation, is important to achieve a diagnosis and to differentiate KHE from more common vascular lesions (e.g., infantile hemangioma). Sirolimus therapy is emerging as a promising treatment for unresectable KHE.

Kaposi's sarcoma herpesvirus-induced endothelial cell reprogramming supports viral persistence and contributes to Kaposi's sarcoma tumorigenesis.

Kaposi's sarcoma (KS) is an endothelial tumor causally linked to Kaposi's sarcoma herpesvirus (KSHV) infection. At early stages of KS, inflammation and aberrant neoangiogenesis are predominant, while at late stages the disease is characterized by the proliferation of KSHV-infected spindle cells (SC). Since KSHV infection modifies the endothelial cell (EC) identity, the origin of SCs remains elusive. Yet, pieces of evidence indicate the lymphatic origin. KSHV-infected ECs display increased proliferative, angiogenic and migratory capacities which account for KS oncogenesis. Here we propose a model in which KSHV reprograms the EC identity, induces DNA damage and establishes a dysregulated gene expression program involving interplay of latent and lytic genes allowing continuous reinfection of ECs attracted to the tumor by the secretion of virus-induced cellular factors.

IKKγ-Mimetic Peptides Block the Resistance to Apoptosis Associated with Kaposi's Sarcoma-Associated Herpesvirus Infection.

Primary effusion lymphoma (PEL) is a lymphogenic disorder associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Key to the survival and proliferation of PEL is the canonical NF-κB pathway, which becomes constitutively activated following overexpression of the viral oncoprotein KSHV vFLIP (ks-vFLIP). This arises from its capacity to form a complex with the modulatory subunit of the IκB kinase (IKK) kinase, IKKγ (or NEMO), resulting in the overproduction of proteins that promote cellular survival and prevent apoptosis, both of which are important drivers of tumorigenesis. Using a combination of cell-based and biophysical assays together with structural techniques, we showed that the observed resistance to cell death is largely independent of autophagy or major death receptor signaling pathways and demonstrated that direct targeting of the ks-vFLIP-IKKγ interaction both in cells and in vitro can be achieved using IKKγ-mimetic peptides. Our results further reveal that these peptides not only induce cell killing but also potently sensitize PEL to the proapoptotic agents tumor necrosis factor alpha and etoposide and are the first to confirm ks-vFLIP as a tractable target for the treatment of PEL and related disorders.IMPORTANCE KSHV vFLIP (ks-vFLIP) has been shown to have a crucial role in cellular transformation, in which it is vital for the survival and proliferation of primary effusion lymphoma (PEL), an aggressive malignancy associated with infection that is resistant to the majority of chemotherapeutic drugs. It operates via subversion of the canonical NF-κB pathway, which requires a physical interaction between ks-vFLIP and the IKK kinase modulatory subunit IKKγ. While this interaction has been directly linked to protection against apoptosis, it is unclear whether the suppression of other cell death pathways implicated in ks-vFLIP pathogenesis is an additional contributor. We demonstrate that the interaction between ks-vFLIP and IKKγ is pivotal in conferring resistance to apoptosis. Additionally, we show that the ks-vFLIP-IKKγ complex can be disrupted using peptides leading to direct killing and the sensitization of PEL cells to proapoptotic agents. Our studies thus provide a framework for future therapeutic interventions.

Updating vital status by tracking in the community among patients with epidemic Kaposi sarcoma who are lost to follow-up in sub-Saharan Africa.

BACKGROUND: Throughout most of sub-Saharan Africa (and, indeed, most resource-limited areas), lack of death registries prohibits linkage of cancer diagnoses and precludes the most expeditious approach to determining cancer survival. Instead, estimation of cancer survival often uses clinical records, which have some mortality data but are replete with patients who are lost to follow-up (LTFU), some of which may be caused by undocumented death. The end result is that accurate estimation of cancer survival is rarely performed. A prominent example of a common cancer in Africa for which survival data are needed but for which frequent LTFU has precluded accurate estimation is Kaposi sarcoma (KS). METHODS: Using electronic records, we identified all newly diagnosed KS among HIV-infected adults at 33 primary care clinics in Kenya, Uganda, Nigeria, and Malawi from 2009 to 2012. We determined those patients who were apparently LTFU, defined as absent from clinic for ≥90 days at database closure and unknown to be dead or transferred. Using standardized protocols which included manual chart review, telephone calls, and physical tracking in the community, we attempted to update vital status amongst patients who were LTFU. RESULTS: We identified 1222 patients with KS, of whom 440 were LTFU according to electronic records. Manual chart review revealed that 18 (4.1%) were classified as LFTU due to clerical error, leaving 422 as truly LTFU. Of these 422, we updated vital status in 78%; manual chart review was responsible for updating in 5.7%, telephone calls in 26%, and physical tracking in 46%. Among 378 patients who consented at clinic enrollment to be tracked if they became LTFU and who had sufficient geographic contact/locator information, we updated vital status in 88%. Duration of LTFU was not associated with success of tracking, but tracking success was better in Kenya than the other sites. CONCLUSION: It is feasible to update vital status in a large fraction of patients with HIV-associated KS in sub-Saharan Africa who have become LTFU from clinical care. This finding likely applies to other cancers as well. Updating vital status amongst lost patients paves the way towards accurate determination of cancer survival.

KSHV microRNAs: Tricks of the Devil.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), a vascular tumor frequently found in immunodeficient individuals. KSHV encodes 12 pre-microRNAs (pre-miRNAs), which are processed into 25 mature microRNAs (miRNAs). KSHV miRNAs maintain KSHV latency, enhance angiogenesis and dissemination of the infected cells, and interfere with the host immune system by regulating viral and cellular gene expression, ultimately contributing to KS development. In this review, we briefly introduce the biogenesis of miRNAs and then describe the recent advances in defining the roles and mechanisms of action of KSHV miRNAs in KS development.

Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded microRNAs promote matrix metalloproteinases (MMPs) expression and pro-angiogenic cytokine secretion in endothelial cells.

The human oncogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to Kaposi's sarcoma (KS), a tumor of endothelial cells characterized by angiogenesis and invasiveness. KSHV genome encodes 25 mature microRNAs (miRNAs), but their roles in KSHV-induced tumor dissemination and angiogenesis are not fully understood. In this study, we constructed the sensor reporters of KSHV miRNAs and used a luciferase reporter assay to demonstrate the function of the mimics of KSHV miRNAs. Then, we examined the expression of matrix metalloproteinases (MMPs) and pro-angiogenic cytokines that are related to cell migration and angiogenesis in the KSHV 25 miRNAs transfected endothelial cells. We found that all KSHV miRNAs increased the expression of the transcripts of MMP1, MMP13, VEGFA, and VEGFR2 in different degrees, as well as the secretion of VEGFA protein in the supernatant of endothelial cells. Our results reveal that KSHV miRNAs contribute to regulating MMPs and expression of pro-angiogenic factors, thus, suggesting that these miRNAs might play a crucial role in KSHV-induced cell motility and angiogenesis.

[Kaposi's Sarcoma in patients with late HIV diagnosis. Case report and review of literature.] / Sarcoma de Kaposi en paciente con diagnóstico tardío de VIH. Presentación de un caso y revisión.

Kaposi's sarcoma is a limphoangioproliferous tumor described for the first time in the year 1872 by Moritz Kaposi. There are four clinical variants, the classical form, the endemic, the iatrogenic associated to transplantation or immunosuppression and the epidemic associated with AIDS, which will be referred in this publication. In this research,(case, paperwork, investigation) a 31 year old male patient, who was diagnosed AIDS and Kaposi's sarcoma at the same time while in hospital, is described.

El sarcoma de Kaposi es un tumor linfoangioproliferativo descripto por primera vez en el año 1872 por Moritz Kaposi. Hay cuatro variantes clínicas, la forma clásica, la endémica, la iatrogénica asociada a trasplante o inmunosupresión y la epidémica asociada a SIDA, de la cual se hará referencia en esta publicación. Se describe un paciente varón de 31 años, al cual durante la misma internación se hace el diagnóstico de SIDA y de sarcoma de Kaposi.