TASK DEFINITION: In this task, you're given a paragraph from the research paper and your task is to generate a suitable title for the research paper based on the given paper. Under 100 words is a good title length.
PROBLEM: Herpes simplex virus (HSV) infections can be treated with direct acting antivirals like acyclovir and foscarnet, but long-term use can lead to drug resistance, which motivates research into broadly-acting antivirals that can provide a greater genetic barrier to resistance. Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species that inactivate microorganisms. The botanical plant extract Orthoquin TM is a powerful photosensitizer with antimicrobial properties. Here we report that Orthoquin also has antiviral properties. Photoactivated Orthoquin inhibited herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) infection of target cells in a dose-dependent manner across a broad range of sub-cytotoxic concentrations. HSV inactivation required direct contact between Orthoquin and the inoculum, whereas pre-treatment of target cells had no effect. Orthoquin did not cause appreciable damage to viral capsids or premature release of viral genomes, as measured by qPCR for the HSV-1 genome. By contrast, immunoblotting for HSV-1 antigens in purified virion preparations suggested that higher doses of Orthoquin had a physical impact on certain HSV-1 proteins that altered protein mobility or antigen detection. Orthoquin PDI also inhibited the non-enveloped adenovirus (AdV) in a dose-dependent manner, whereas Orthoquin-mediated inhibition of the enveloped vesicular stomatitis virus (VSV) was light-independent. Together, these findings suggest that the broad antiviral effects of Orthoquin-mediated PDI may stem from damage to viral attachment proteins. facilitate attachment and entry into host cells. While HSV-1 and HSV-2 are similar, they share onlỹ 55% nucleotide identity. Lytic HSV infection of a cell begins with initial attachment to negatively charged cell surface heparan sulfate and chondroitin sulfate glycosaminoglycans, followed by stable attachment of viral glycoproteins to cell surface receptors and fusion of the viral envelope to the plasma membrane or internal membranes [2] . Fusion of viral and host membranes enables delivery of the viral nucleocapsid and tegument proteins to the cytoplasm. After the HSV nucleocapsid arrives at the nucleus and delivers the viral genome, HSV genes are expressed in an ordered temporal cascade. Viral egress requires primary envelopment of the genome-containing capsid at the inner nuclear membrane, fusion with the outer nuclear membrane and final envelopment at the trans-Golgi network. Mature virions then exit through the cellular secretory system. All stages of the HSV replication cycle offer potential targets for direct-acting antiviral (DAA) therapy. However, DAAs can be undermined by the emergence of drug resistant mutant viruses. Anti-HSV DAAs acyclovir and foscarnet offer examples of the hazards of drug resistance. These drugs interrupt HSV genome replication by different mechanisms of action. Acyclovir is a nucleoside analogue prodrug that selectively targets HSV infected cells through the action of the HSV thymidine kinase (TK) enzyme, which efficiently phosphorylates acyclovir and facilitates incorporation into nascent viral DNA genomes by the HSV DNA polymerase enzyme; incorporation of acyclovir into viral DNA terminates genome replication [3] . By contrast, the pyrophosphate analogue foscarnet blocks viral genome replication by directly inhibiting HSV DNA polymerase activity [4] . Though resistance to acyclovir occurs at a low prevalence (≤1%) in immunocompetent patients [5], immunocompromised patients experience much higher rates (4-10%) [6] . Unsurprisingly, resistance to acyclovir, and its derivatives, and to foscarnet, has been mapped to mutations in the viral thymidine kinase and the DNA polymerase catalytic subunit, respectively [7] . Currently, Abreva (n-docosanol) is the only over-the-counter topical antiviral for herpes labialis. Abreva is incorporated into the cellular plasma membrane and prevents fusion steps essential for HSV-1 entry into epithelial cells [8] . However, it must be applied repeatedly throughout the day due to rapid plasma membrane turnover and the subsequent loss of n-docosanol [9] . This host-targeted antiviral mechanism prevents development of viral resistance, but Abreva is only approved for perioral lesions, so there is a still a gap in treatment for lesions in other areas of the body. Like Abreva, there is potential for more broadly-acting antiviral drugs that exploit the physical structure of the HSV virion and block early stages of infection, such as attachment and penetration. In this study, we explored the potential of the plant-derived photosensitizing agent Orthoquin TM to mediate photodynamic inactivation (PDI) [10] of virions. The clinical utility of Orthoquin PDI of oral biofilms is an area of active investigation and there is clear potential for wider range of clinical applications. The basis of PDI is the photodynamic effect, which has been exploited in photodynamic therapy (PDT) [11, 12] for treatment of cancers [13] and age-related macular degeneration [14] . In PDT, photosensitizer compounds when exposed to visible light react with oxygen to generate reactive oxygen species (ROS) that include singlet oxygen [15] . ROS damage proteins, nucleic acids and lipids, which can lead to cell death. Some of the most well-known photosensitizing molecules for PDT are based on a tetrapyrrolic core and are found in naturally occurring pigments, such as heme, chlorophyll, and bacteriochlorophyll [16] . The accepted phototoxic mechanism for these types of photosensitizers involves the formation of an excited triplet state upon light absorption that can participate in electron (Type 1) or energy (Type 2) transfer processes. Type 1 electron transfer reactions typically lead to the formation of radical species like superoxide or hydroxyl radicals, whereas Type 2 energy transfer produces cytotoxic singlet oxygen. It is possible for a photosensitizer to initiate both Type 1 and 2 photoprocesses simultaneously, depending on the specific chemistry of the photosensitizing agent and its environment [16] . Due to the high reactivities and short lifetimes of oxidizing molecules, it is expected that only viral structures in close proximity to activated photosensitizing compounds will be affected.

SOLUTION: Photodynamic Inactivation of Herpes Simplex Viruses

PROBLEM: Ability of CD8 + T cells to act as cytolytic effectors and produce IFN-γ was shown to mediate resistance to Toxoplasma gondii in murine models due to recognition of peptides restricted by murine MHC Class I molecules. However, no T. gondii specific HLA-B07 restricted peptides were proven protective against T gondii. Recently, two T gondii-specific HLA-B*0702-restricted T cell epitopes, GRA7 20-28 (LPQFATAAT) and GRA3 27-35 (VPFVVFLVA), displayed highaffinity binding to HLA-B*0702, and elicited IFN-γ from PBMCs of seropositive HLA-B*0702 persons. Herein, these peptides were evaluated to determine whether they could elicit IFN-γ in splenocytes of HLA-B*0702 transgenic mice when administered with adjuvants and protect against subsequent challenge. Peptide-specific IFN-γ producing T cells were identified by ELISPOT and proliferation assays utilizing splenic T lymphocytes from HLA transgenic mice. When HLA-B*0702 mice were immunized with one of the epitopes identified, GRA7 20-28 in conjunction with a universal CD4 + T cell epitope (PADRE) and adjuvants (CD4 + T cell adjuvant, GLA-SE, and TLR2 stimulatory Pam 2 Cys for CD8 + T cells), this immunization induced CD8 + T cells to produce IFN-γ and protected mice against high parasite burden when challenged with T gondii. This work demonstrates feasibility of bioinformatics followed by an empirical approach based on HLA binding to test this biological activity for identifying protective HLA-B*0702 restricted T gondii peptides and adjuvants that elicit protective immune responses in HLA-B*0702 mice.

SOLUTION: Toxoplasma gondii HLA-B*0702 restricted GRA7 20-28 peptide with adjuvants and an universal helper T cell epitope elicits CD8 + T cells producing IFN-γ and reduces parasite burden in HLA- B*0702 mice 1 NIH Public Access

PROBLEM: Loperamide is an antidiarrheal drug that targets μ-opioid receptors and calcium channels. A previous report demonstrated that loperamide induces autophagy and enhances antimicrobial activity towards M. tuberculosis in murine and human alveolar macrophages. The aim of this study was to evaluate the immunomodulatory effects of loperamide on macrophages with respect to cytokine and antimicrobial peptide production during mycobacterial infection. We infected monocyte-derived macrophages (macrophages) with M. tuberculosis H37Rv at a multiplicity of infection (MOI) of 5 and treated the cells with 3 μM loperamide. Cytokine production in the supernatants of 24-h cultures and gene expression of the cytokines TNFα, IL1β and IL10 and the antimicrobial peptides LL37 and bactericidal/permeability increasing protein (BPI) in the cell lysates was measured. Intracellular bacterial loads were evaluated by enumerating colony-forming units 3 days posttreatment for M. tuberculosis and 24 h posttreatment for M. smegmatis. We observed that loperamide exerted an immunomodulatory effect on TNFα production in human macrophages infected with M. tuberculosis and that these responses were independent of the bacteria, as they also occurred when macrophages were infected with M. smegmatis and to a lesser extent with M. bovis. In addition, antibacterial mechanisms triggered by loperamide induced a significant reduction in bacterial load and an upregulation of BPI and LL37 gene expression. Thus, our results show that loperamide exerts immunomodulatory effects, which supports its use for additional medical conditions other than diarrhea.

SOLUTION:
Antimicrobial and immunomodulatory activity induced by loperamide in mycobacterial infections