Sandra Martin-Latil

Early Phosphatidylinositol 3-Kinase/Akt Pathway Activation Limits Poliovirus-Induced JNK-Mediated Cell Death

ABSTRACT Poliovirus (PV)-induced apoptosis seems to play a major role in tissue injury in the central nervous system (CNS). We have previously shown that this process involves PV-induced Bax-dependent mitochondrial dysfunction mediated by early JNK activation in IMR5 neuroblastoma cells. We showed here that PV simultaneously activates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signaling pathway in these cells, limiting the extent of JNK activation and thereby cell death. JNK inhibition is associated with PI3K-dependent negative regulation of the apoptosis signal-regulating kinase 1, which acts upstream from JNK in PV-infected IMR5 cells. In poliomyelitis, this survival pathway may limit the spread of PV-induced damage in the CNS.

Poliovirus induces Bax-dependent cell death mediated by c-Jun NH2-terminal kinase.

ABSTRACT Poliovirus (PV) is the causal agent of paralytic poliomyelitis, a disease that involves the destruction of motor neurons associated with PV replication. In PV-infected mice, motor neurons die through an apoptotic process. However, mechanisms by which PV induces cell death in neuronal cells remain unclear. Here, we demonstrate that PV infection of neuronal IMR5 cells induces cytochrome c release from mitochondria and loss of mitochondrial transmembrane potential, both of which are evidence of mitochondrial outer membrane permeabilization. PV infection also activates Bax, a proapoptotic member of the Bcl-2 family; this activation involves its conformational change and its redistribution from the cytosol to mitochondria. Neutralization of Bax by vMIA protein expression prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. Interestingly, we also found that c-Jun NH2-terminal kinase (JNK) is activated soon after PV infection and that the PV-cell receptor interaction alone is sufficient to induce JNK activation. Moreover, the pharmacological inhibition of JNK by SP600125 inhibits Bax activation and cytochrome c release. This is, to our knowledge, the first demonstration of JNK-mediated Bax-dependent apoptosis in PV-infected cells. Our findings contribute to our understanding of poliomyelitis pathogenesis at the cellular level.

Bax Is Activated during Rotavirus-Induced Apoptosis through the Mitochondrial Pathway

ABSTRACT Rotaviruses are the leading cause of infantile viral gastroenteritis worldwide. Mature enterocytes of the small intestine infected by rotavirus undergo apoptosis, and their replacement by less differentiated dividing cells probably leads to defective absorptive function of the intestinal epithelium, which, in turn, contributes to osmotic diarrhea and rotavirus pathogenesis. Here we show that infection of MA104 cells by the simian rhesus rotavirus strain RRV induced caspase-3 activation, DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase; all three phenomena are features of apoptosis. RRV induced the release of cytochrome c from mitochondria to the cytosol, indicating that the mitochondrial apoptotic pathway was activated. RRV infection of MA104 cells activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change. Most importantly, Bax-specific small interfering RNAs partially inhibited cytochrome c release in RRV-infected cells. Thus, mitochondrial dysfunction induced by rotavirus is Bax dependent. Apoptosis presumably leads to impaired intestinal functions, so our findings contribute to improving our understanding of rotavirus pathogenesis at the cellular level.

Transcytosis of HTLV-1 across a tight human epithelial barrier and infection of subepithelial dendritic cells

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. In addition to blood transfusion and sexual transmission, HTLV-1 is transmitted mainly through prolonged breastfeeding, and such infection represents a major risk for the development of adult T-cell leukemia/lymphoma. Although HTLV-1-infected lymphocytes can be retrieved from maternal milk, the mechanisms of HTLV-1 transmission through the digestive tract remain unknown. In the present study, we assessed HTLV-1 transport across the epithelial barrier using an in vitro model. Our results show that the integrity of the epithelial barrier was maintained during coculture with HTLV-1-infected lymphocytes, because neither morphological nor functional alterations of the cell monolayer were observed. Enterocytes were not susceptible to HTLV-1 infection, but free infectious HTLV-1 virions could cross the epithelial barrier via a transcytosis mechanism. Such virions were able to infect productively human dendritic cells located beneath the epithelial barrier. Our data indicate that HTLV-1 crosses the tight epithelial barrier without disruption or infection of the epithelium to further infect target cells such as dendritic cells. The present study provides the first data pertaining to the mode of HTLV-1 transport across a tight epithelial barrier, as can occur during mother-to-child HTLV-1 transmission during breastfeeding.

Mother-to-Child Transmission of HTLV-1 Epidemiological Aspects, Mechanisms and Determinants of Mother-to-Child Transmission

Human T-cell Lymphotropic Virus type 1 (HTLV-1) is a human retrovirus that infects at least 5–10 million people worldwide, and is the etiological agent of a lymphoproliferative malignancy; Adult T-cell Leukemia/Lymphoma (ATLL); and a chronic neuromyelopathy, HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), as well as other inflammatory diseases such as infective dermatitis and uveitis. Besides sexual intercourse and intravenous transmission, HTLV-1 can also be transmitted from infected mother to child during prolonged breastfeeding. Some characteristics that are linked to mother-to-child transmission (MTCT) of HTLV-1, such as the role of proviral load, antibody titer of the infected mother, and duration of breastfeeding, have been elucidated; however, most of the mechanisms underlying HTLV-1 transmission during breast feeding remain largely unknown, such as the sites of infection and cellular targets as well as the role of milk factors. The present review focuses on the latest findings and current opinions and perspectives on MTCT of HTLV-1.

Reduced Apoptosis in Human Intestinal Cells Cured of Persistent Poliovirus Infection

ABSTRACT Cells cured of persistent virus infection can be used to investigate cellular pathways of resistance to viral cytopathic effects. Persistent poliovirus (PV) infections were established in human intestinal Caco-2 cells, and spontaneously cured cell cultures were obtained. Two cell clones, cl6 and b13, cured of type 3 PV mutant infection and their parental Caco-2 cells were compared for susceptibility to PV infection, PV receptor CD155 expression, capacity to differentiate into polarized enterocytes, and PV-, staurosporine-, and actinomycin D-induced apoptosis. Our results strongly suggest that cells that are partially resistant to apoptosis can be selected during persistent virus infection.

Apoptotic signaling cascades operating in poliovirus-infected cells.

The flaccid paralyses characteristic of poliomyelitis are a direct consequence of the infection of motor neurons with poliovirus (PV). In PV-infected mice, motor neurons die by apoptosis. However, the mechanisms by which PV induces cell death in neurons remain unclear. Analyses of the apoptotic pathways induced by PV infection in several cell lines have demonstrated that mitochondria play a key role in PV-induced apoptosis. Furthermore, mitochondrial dysfunction results from an imbalance between pro- and anti-apoptotic pathways. We present here an overview of the many studies of PV-induced apoptosis carried out in recent years and discuss the contribution of these studies to our understanding of poliomyelitis.

Immunohistochemical and virological features of HTLV-1-associated myosites: a study of 13 patients from West Indies and Africa

Immunohistochemical and virological features of HTLV-1-associated myosites: a study of 13 patients from West Indies and Africa Marion Desdouits, Olivier Cassar, Thierry Maisonobe, Alexandra Desrames, Achille Aouba, Olivier Hermine, Jacqueline Mikol, Marc Polivka, Isabelle Penisson-Besnier, Pascale Marcorelles, Fabien Zagnoli, Thomas Papo, Arnaud Lacour, Zahir Amoura, Julien Haroche, Patrick Cherin, Antonio Texeira, Anne-Sophie Morin, Franck Mortreux, Eric Wattel, Michel Huerre, Marie-Christine Cumont, Huot Khun, Sylviane Bassot, Sandra Martin-Latil, Graham Taylor, Antoine Gessain, Simona Ozden, Pierre-Emmanuel Ceccaldi

Mother-to-child transmission of HTLV-1: in vitro

Human T-Cell Leukemia Virus type 1 (HTLV-1), that infects around 15 million people world wide, is the causative agent of adult T-cell leukemia/lymphoma and HTLV1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Besides horizontal transmission, HTLV-1 is transmitted vertically mainly through breastfeeding. This maternal transmission via breast milk appears to be the dominant mode of HTLV-1 spread in the high endemic areas, and is correlated with the presence of HTLV-1 infected cells (lymphocytes, epithelial cells...) in the milk of infected mothers.

Mother-to-child transmission of HTLV-1: in vitro study of HTLV-1 passage across a tight human epithelial barrier

Background Besides horizontal transmission, HTLV-1 is transmitted vertically mainly through prolonged breastfeeding. Maternal transmission via breast milk is the dominant mode of HTLV-1 spread in high endemic areas, and is inked to the presence of HTLV-1 infected cells (lymphocytes, epithelial cells..) in the milk. Infection in young childhood by such mean appears to be a major risk factor for development of ATL in adults. Materials and methods We developed an in vitro model of epithelial barrier (Caco-2 human enterocytic cell line) to assess the mode of passage of HTLV-1 through the digestive tract. Integrity of the barrier was checked by ultrastructural approach, measurement of the trans-epithelial resistance (TER), and diffusion of fluorescently labeled molecules. Results When enterocytes were co-cultured with HTLV-1infected lymphocytes, no structural modifications were detected in intercellular tight junctions. Moreover, the functional integrity of the epithelial barrier was maintained since no TER change was detected in the presence of infected lymphocytes, and passage of small fluorescent markers was unaffected. Although enterocytes were not found to be susceptible to HTLV-1 infection, free infectious HTLV-1 virions were detected in the basal compartment, and such a passage was temperaturedependent, suggesting a transcytotic mechanism of passage. When human dendritic cells were added to the basal compartment, they were found to be productively infected by HTLV-1 that had crossed the epithelial barrier.