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In this paper, we present strongly geodesic preinvexity on Riemannian manifolds (RM) and strongly η-invexity of order m on RM. Furthermore, we define strongly invariant η-monotonicity of order m on RM. Under Condition C, an important characterization of these functions are studied. We construct several non-trivial examples in support of these definitions. Afterwords, an important and significant characterization of a strict η-minimizers (η-minimizers)of order m for MOP and a solution to the variational like-inequality problem (VVLIP) has been derived.

In the context of chronic viral infections, the hepatic microenvironment dictates the outcome of the disease by influencing propagation of virus and regulation of cytotoxic CD8+ T cell response. Nevertheless, such regulation could be beneficial as it resolves the disease or could be detrimental as it causes liver pathological consequences. Liver pathology is a hallmark of chronic viral infection in both human and murine models. Such models show viral infection of hepatocytes and subsequent direct hepatic damage. Other compelling studies showed that liver injury was a consequence of overshooting CD8+ T cells response in experimental mice, so-called immune-mediated liver pathology. This review highlights the viral-induced immune mediated aspects of liver pathology based on the lymphocytic choriomeningitis virus (LCMV) and Hepatitis virus settings. CA Hamdan

The replication of viruses in secondary lymphoid organs guarantees sufficient amounts of pattern-recognition receptor ligands and antigens to activate the innate and adaptive immune system. Viruses with broad cell tropism usually replicate in lymphoid organs, however, whether a virus with a narrow tropism relies on replication in the secondary lymphoid organs to activate the immune system remains not well studied. In this study, we used the artificial intravenous route of infection to determine whether Influenza A virus (IAV) replication can occur in secondary lymphatic organs (SLO) and whether such replication correlates with innate immune activation. Indeed, we found that IAV replicates in secondary lymphatic tissue. IAV replication was dependent on the expression of Sialic acid residues in antigen-presenting cells and on the expression of the interferon-inhibitor UBP43 (Usp18). The replication of IAV correlated with innate immune activation, resulting in IAV eradication. The genetic deletion of Usp18 curbed IAV replication and limited innate immune activation. In conclusion, we found that IAV replicates in SLO, a mechanism which allows innate immune activation.

Immune activation within the tumor is one promising approach to induce immune-mediated tumor regression. Viruses are promising approaches to induce tumor-specific immune activation, however not all tumor types respond to virotherapy and mechanisms explaining such differences remains to be defined. Here, by using the lymphocytic choriomeningitis virus (LCMV) in different tumor cell lines, we found that some human melanoma cell lines responded strongly with CCL5 production especially mamel-86A responded very well to the arenavirus therapy, when the mamel-86A tumor bearing NodScid mice were treated with the LCMV there was the complete tumor regression and mice were tumor free at one point, but some tumors like mamel-51 showed massive resistance to the arenavirus therapy, To further address this question of robust tumor regression in case of mamel-86A and strong resistance towards LCMV therapy by mamel-51. We performed both in-vivo and in-vitro experiments and we discovered that the tumors that responded well to the LCMV therapy showed enhanced CCL5 production upon LCMV infection while as in case of non-responding tumors there was indigent CCL5 production, this variation in the chemokine profile upon the viral therapy further gave us the clue that there must be different immune cells infiltrate in the tumor microenvironment both in responding and non-responding tumor models and upon further investigation we discovered that there is massive NK cell infiltrate to the tumor site upon LCMV infection but this scenario only happens in case of responding tumor (Mamel-86A) while as in case of non-responding tumor there was very poor NK cell infiltrate, so higher CCL5 drives more NK cells to the site of the tumor and vice versa. The next interesting finding in our study was that the production of CCL5 in the Mamel-86A tumor cells is dependent on PI3K pathway; blockade of PI3K by using the inhibitors abrogates the production of CCL5. To further, address this massive antitumor effects we used NK cell deficient mice, these mice showed faster tumor growth and poor antitumor effects even after LCMV therapy but since the antitumor effects in our experimental model is also linked to the CCL5, this further prompted us to look how the tumors will be behave upon the blockage of CCR5, upon in-vivo experimental settings we found out that blockade of CCL5 leads to the enhanced growth of tumor Thus we can say depletion of NK cells or CCL5 abolished anti-tumoral effects of virotherapy. In conclusion, we identified CCL5 and NK cell mediated cytotoxicity as a new mechanism leading to regression of melanoma and explaining differences in the immunological response to virotherapy., Die Immunaktivierung innerhalb des Tumors ist ein vielversprechender Ansatz, um eine immunvermittelte Tumorregression zu induzieren. Viren sind vielversprechende Ansätze zur Induktion einer tumorspezifischen Immunaktivierung, jedoch sprechen nicht alle Tumortypen auf eine Virotherapie an und die Mechanismen, die diese Unterschiede erklären würden, müssen noch identifiziert werden. Hier fanden wir unter Verwendung des lymphozytären Choriomeningitis-Virus (LCMV) in verschiedenen Tumorzelllinien heraus, dass einige humane Melanomzelllinien wie MaMel-86a sehr gut auf die Arenavirus- Therapie ansprachen. Während die LCMV Behandlung MaMel-86a Tumor tragender NodScid Mäuse, die mit einer starken CCL5-Produktion reagierten, zu einer vollständigen Tumorregression und sogar teilweise tumorfreien Mäusen führten, zeigten manche Tumoren wie das MaMel-51 eine massive Resistenz gegen die Arenavirus Therapie. Um die Fragestellung sowohl um diese starke Tumorregression der MaMel 86a Tumoren, als auch die starke Resistenz der MaMel-41 Tumoren gegen die LCMV Therapie weiter zu untersuchen führten wir sowohl in-vivo als auch in-vitro Experimente durch und entdeckten, dass die Tumoren, die gut auf die LCMV-Therapie ansprachen, eine erhöhte CCL5-Produktion nach LCMV-Infektion zeigten, während im Falle von nicht ansprechenden Tumoren eine schwache CCL5-Produktion auftrat. Ferner ergab das Chemokinprofil nach der Virustherapie den Hinweis, dass sowohl in ansprechenden als auch in nichtansprechenden Tumormodellen unterschiedliche Immunzellen die Tumormikroumgebung infiltrieren. Nach weiteren Untersuchungen stellten wir fest, dass die Tumoren nach LCMV-Infektion massiv mit NK-Zellen infiltriert sind, dieses Szenario aber nur im Falle eines ansprechenden Tumors (Mamel-86A) auftritt, während im Falle eines nicht ansprechenden Tumors eine sehr schlechte NK-Zell- Infiltration vorlag, so dass ein höheres CCL5 mehr NK-Zellen in den Tumor lockt und umgekehrt. Der nächste interessante Befund in unserer Studie war, dass die Produktion von CCL5 in den Mamel-86A-Tumorzellen vom PI3K-Signalweg abhängt. Die Blockade von PI3K durch Verwendung von Inhibitoren unterbindet die Produktion von CCL5. Um diesem massiven antitumoralen Effekten entgegenzuwirken verwendeten wir Mäuse ohne NK- Zellen. Diese Mäuse zeigten auch nach LCMV-Therapie ein schnelleres Tumorwachstum und schwache Antitumoreffekte. Da die antitumoralen Effekte in unserem Versuchsmodell jedoch auch mit CCL5 in Verbindung standen, führte uns das dazu, sich anzuschauen, wie sich die Tumoren bei einer Blockade von CCL5 verhalten. In vivo fanden wir heraus, dass eine Blockade von CCL5 zu einem verstärkten Wachstum des Tumors führt. Man kann also sagen, dass die Depletion von NK-Zellen oder CCL5 die antitumoralen Wirkungen der Virotherapie aufhob. Zusammenfassend identifizierten wir die CCL5- und NK-Zell-vermittelte Zytotoxizität als neuen Mechanismus, der zur Regression des Melanoms und zur Erklärung der Unterschiede in der immunologischen Reaktion auf Virotherapie führt.

Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection. OA Förderung 2021