Mesenchymal Stem Cell-Derived Exosomes Attenuate Murine Cytomegalovirus-Infected Pneumonia via NF-κB/NLRP3 Signaling Pathway.

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.

Therapeutic potentials of CRISPR-Cas genome editing technology in human viral infections.

Viral infections are a common cause of morbidity worldwide. The emergence of Coronavirus Disease 2019 (COVID-19) has led to more attention to viral infections and finding novel therapeutics. The CRISPR-Cas9 system has been recently proposed as a potential therapeutic tool for the treatment of viral diseases. Here, we review the research progress in the use of CRISPR-Cas technology for treating viral infections, as well as the strategies for improving the delivery of this gene-editing tool in vivo. Key challenges that hinder the widespread clinical application of CRISPR-Cas9 technology are also discussed, and several possible directions for future research are proposed.

Nanotechnology Frontiers in γ-Herpesviruses Treatments.

Epstein-Barr Virus (EBV) and Kaposi's sarcoma associated-herpesvirus (KSHV) are γ-herpesviruses that belong to the Herpesviridae family. EBV infections are linked to the onset and progression of several diseases, such as Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC), and lymphoproliferative malignancies arising in post-transplanted patients (PTDLs). KSHV, an etiologic agent of Kaposi's sarcoma (KS), displays primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Many therapeutics, such as bortezomib, CHOP cocktail medications, and natural compounds (e.g., quercetin or curcumin), are administrated to patients affected by γ-herpesvirus infections. These drugs induce apoptosis and autophagy, inhibiting the proliferative and cell cycle progression in these malignancies. In the last decade, many studies conducted by scientists and clinicians have indicated that nanotechnology and nanomedicine could improve the outcome of several treatments in γ-herpesvirus-associated diseases. Some drugs are entrapped in nanoparticles (NPs) expressed on the surface area of polyethylene glycol (PEG). These NPs move to specific tissues and exert their properties, releasing therapeutics in the cell target. To treat EBV- and KSHV-associated diseases, many studies have been performed in vivo and in vitro using virus-like particles (VPLs) engineered to maximize antigen and epitope presentations during immune response. NPs are designed to improve therapeutic delivery, avoiding dissolving the drugs in toxic solvents. They reduce the dose-limiting toxicity and reach specific tissue areas. Several attempts are ongoing to synthesize and produce EBV vaccines using nanosystems.

New Insights into the Management of an EHV-1 (Equine Hospital) Outbreak.

In May 2018, Wolvega Equine Hospital (WEH) experienced an EHV-1 outbreak. This outbreak caused significant economic losses and negative publicity for the hospital. How should hospitals prepare themselves for these outbreaks and prevent shedding of the virus on multiple neighboring premises? The hospital transformed most of its activities into mobile practice and the entire infected hospital population was moved to a separate remote location. The hospital was cleaned and disinfected according to the latest recommendations before reopening. Four neighboring professional equine businesses and three privately owned premises were affected by the spread of the virus from the hospital population and initiated quarantine restrictions. Equine hospitals should prepare themselves for EHV-1 outbreaks as the intake of the virus cannot be prevented. A management protocol should include public information protocols, swift client information and quarantine measures that ensure quick containment of the outbreak. Timely reopening of the hospital can be achieved by rehousing the contaminated population. It should also include good regulations with clients and a properly carried out release protocol. Equine sports organizations should establish sufficient vaccination coverage in order to decrease the frequency of EHV-1 outbreaks.

Viral Venereal Diseases of the Skin.

Viral venereal diseases remain difficult to treat. Human papilloma virus (HPV) and herpes simplex virus (HSV) are two common viral venereal diseases. HPV infections are characterized by anogenital warts and less commonly by premalignant or malignant lesions. HSV infections classically present as grouped vesicles on an erythematous base with associated burning or pain; however, immunosuppressed patients may have atypical presentations with nodular or ulcerative lesions. This review discusses the epidemiology, diagnosis, and management of anogenital HPV and HSV infections with an emphasis on treatment modalities for the practicing dermatologist. Diagnosis of these diseases typically relies on clinical assessment, although multiple diagnostic techniques can be utilized and are recommended when diagnosis is uncertain or evaluating an individual with increased risk of malignancy. Management of HPV and HSV infections involves appropriate counseling, screening, and multiple treatment techniques. Particularly for HPV infections, a practitioner may need to use a combination of techniques to achieve the desired outcome.

ACUTE HEMORRHAGIC DISEASE DUE TO ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS 3A INFECTION IN FIVE AFRICAN ELEPHANTS (LOXODONTA AFRICANA) AT ONE NORTH AMERICAN ZOOLOGICAL INSTITUTION.

Acute hemorrhagic disease caused by elephant endotheliotropic herpesvirus (EEHV) infection is well recognized as a major threat to young Asian elephants (Elephas maximus) but has been less frequently documented in African elephants (Loxodonta africana). This report describes five sequential cases of EEHV3A infection in African elephants in managed care at one institution. All elephants developed disease within a 4-mo period. The first two cases were 6.5- and 7.5-yr-old females that presented with depressed mentation, anorexia, hematuria, and diarrhea. Both elephants died within 48-72 hr of the onset of illness despite treatment. Postmortem findings included widespread edema, ascites, and extensive petechiae and ecchymoses on the heart, liver, and spleen and within the gastrointestinal and urogenital tracts. Histologic examination identified disseminated vascular necrosis with edema, hemorrhage, and rare endothelial cell intranuclear inclusions typical of herpesvirus in multiple organs. The third and fourth cases were a 13-yr-old male and a 12-yr-old female that presented with minimal to no clinical signs, but with marked changes in hematologic parameters and high viremia detected by quantitative polymerase chain reaction (qPCR). Both elephants survived the infection with early and aggressive treatment. The fifth case was a 37-yr-old female that presented with lethargy and a decreased appetite. Low viremia was detected by qPCR, and mild to moderate hematologic changes were noted. Early treatment resulted in a successful outcome. This case series documents the first known reports of clinical disease and fatality associated with EEHV3A in African elephants.

PD-1-specific "Blocking" antibodies that deplete PD-1+ T cells present an inconvenient variable in preclinical immunotherapy experiments.

Therapeutic antibodies blocking PD-1-/PD-L1 interaction have achieved remarkable clinical success in cancer. In addition to blocking a target molecule, some isotypes of antibodies can activate complement, NK cells or phagocytes, resulting in death of the cell expressing the antibody's target. Human anti-PD-1 therapeutics use antibody isotypes designed to minimize such antibody-dependent lysis. In contrast, anti-PD-1 reagents used in mice are derived from multiple species, with different isotypes, and are not engineered to reduce target cell death: few studies analyze or discuss how antibody species and isotype may impact data interpretation. We demonstrate here that anti-PD-1 therapy to promote activation and proliferation of murine PD-1-expressing CD8 T cells sometimes led instead to a loss of antigen specific cells. This phenomenon was seen in two tumor models and a model of virus infection, and varied with the clone of anti-PD-1 antibody. Additionally, we compared competition among anti-PD-1 clones to find a combination that allows detection of PD-1-expressing cells despite the presence of blocking anti-PD1 antibodies in vivo. These data bring attention to the possibility of unintended target cell depletion with some commonly used anti-mouse PD-1 clones, and should provide a valuable resource for the design and interpretation of anti-PD-1 studies in mice.

Viral Infections in Burn Patients: A State-Of-The-Art Review.

Infections that are triggered by the accompanying immunosuppression in patients with burn wounds are very common regardless of age. Among burn patients, the most frequently diagnosed infections include the bacterial ones primarily caused by Pseudomonas aeruginosa or Klebsiella pneumonia, as well as fungal infections with the etiology of Candida spp. or Aspergillus spp. Besides, burn wounds are highly susceptible to viral infections mainly due to the impaired immune responses and defective functions of the immune cells within the wound microenvironment. The most prevalent viruses that invade burn wounds include herpes simplex virus (HSV), cytomegalovirus (CMV), human papilloma virus (HPV), and varicella zoster virus (VZV). Likewise, less prevalent infections such as those caused by the orf virus or Epstein-Barr Virus (EBV) might also occur in immunosuppressed burn patients. Viral infections result in increased morbidity and mortality rates in severely burned patients. Additionally, a positive correlation between the hospitalization duration and the severity of the viral infection has been demonstrated. Viral infections trigger the occurrence of various complications, ranging from mild symptoms to even fatal incidents. Accurate detection of viral infection is of great clinical importance because of the possibility for a quicker introduction of proper treatment therapy and shortening of hospitalization time. The aim of this paper is to provide a comprehensive review of the literature and summarize the findings regarding the most common viral infections in immunosuppressed burn patients.

Human herpes virus 8-positive germinotropic lymphoproliferative disorder: first case diagnosed in the UK, literature review and discussion of treatment options.

We present this case of human herpes virus 8-positive germinotropic lymphoproliferative disorder in a 20-year-old woman seen in the surgical oncology clinic for localised lymphadenopathy. This is the first case to be reported in the UK, and we discuss it along with a literature review including investigations and treatment options. This will demonstrate the importance of preoperative workup and multidisciplinary teamwork in deciding management plans and serve as a guide for future encounters of this rare condition in clinical practice.

Update on Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) - review.

Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is one of the few pathogens recognized as direct carcinogen, being involved in the pathogenesis of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. KSHV is a relatively recently discovered virus, with still limited possibilities for diagnosis and treatment. Therefore, ongoing studies are trying to answer the main issues related to the management of KSHV infection and its associated diseases. This review updates the current knowledge of the KSHV infection, discussing aspects related to epidemiology, virological features, clinical manifestations, diagnosis and treatment.

Germinotropic lymphoproliferative disorder: a systematic review.

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms "germinotropic" and "lymphoproliferative disorder." Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.

Overview of Castleman disease.

Castleman disease (CD) describes a group of at least 4 disorders that share a spectrum of characteristic histopathological features but have a wide range of etiologies, presentations, treatments, and outcomes. CD includes unicentric CD (UCD) and multicentric CD (MCD), the latter of which is divided into idiopathic MCD (iMCD), human herpes virus-8 (HHV8)-associated MCD (HHV8-MCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS)-associated MCD (POEMS-MCD). iMCD can be further subclassified into iMCD-thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS). Advances in diagnosis, classification, pathogenesis, and therapy are substantial since the original description of UCD by Benjamin Castleman in 1954. The advent of effective retroviral therapy and use of rituximab in HHV8-MCD have improved outcomes in HHV8-MCD. Anti-interleukin-6-directed therapies are highly effective in many iMCD patients, but additional therapies are required for refractory cases. Much of the recent progress has been coordinated by the Castleman Disease Collaborative Network (CDCN), and further progress will be made by continued engagement of physicians, scientists, and patients. Progress can also be facilitated by encouraging patients to self-enroll in the CDCN's ACCELERATE natural history registry (#NCT02817997; www.CDCN.org/ACCELERATE).

miR-1929-3p Overexpression Alleviates Murine Cytomegalovirus-Induced Hypertensive Myocardial Remodeling by Suppressing Ednra/NLRP3 Inflammasome Activation.

MicroRNAs (miRNAs) play crucial roles in the development of essential hypertension (EH). Previously, we found that the expression of miR-1929-3p was decreased in C57BL/6 mice with hypertension induced by murine cytomegalovirus (MCMV). In this study, we explored the role of miR-1929-3p in hypertension myocardial remodeling in MCMV-infected mice. First, we measured MCMV DNA and host IgG and IgM after infection and determined the expression of miR-1929-3p and its target gene endothelin A receptor (Ednra) mRNA in the myocardium of mice. Then, we performed invasive blood pressure (BP) monitoring. Heart-to-body weight ratio (HW/BW%), along with mRNA levels of B-type natriuretic peptide (BNP) and beta myosin heavy chain (ß-MHC), revealed myocardial remodeling. Hematoxylin/eosin and Masson's trichrome staining indicated morphological changes in the myocardium. Cardiac function was assessed via echocardiography. Moreover, MCMV-infected mice were injected with recombinant adeno-associated virus- (rAAV-) miR-1929-3p overexpression vector. Immunohistochemistry and western blotting showed the expression of Ednra and the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. And enzyme-linked immunosorbent assay (ELISA) revealed the concentrations of endothelin-1 (ET-1), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18). In this study, we found that decreased expression of miR-1929-3p in MCMV-infected mice induced high BP and further development of myocardial remodeling cardiac function injury through increased expression of Ednra. Strikingly, overexpression of miR-1929-3p ameliorated these pathological changes of the heart. The positive effect was shown to be associated with inhibition of NLRP3 inflammasome activation and decreased expression of key proinflammatory cytokine IL-1ß. Collectively, these results indicate that miR-1929-3p overexpression may effectively alleviate EH myocardial remodeling by suppressing Ednra/NLRP3 inflammasome activation in MCMV-infected mice.

Update on oncogenesis and therapy for Kaposi sarcoma.

PURPOSE OF REVIEW: This review is an update of the recent findings on pathophysiology of Kaposi sarcoma, the role of HHV-8 in Kaposi sarcoma pathogenesis and to summarize the recent advances in the treatment of Kaposi sarcoma and the role of immunity to control the disease. RECENT FINDINGS: The causal agent of Kaposi sarcoma is HHV-8 and the mechanism by which HHV-8 drives the tumor development is unique. HHV-8 is not a classic oncogenic virus and the disease is an opportunistic tumor responding to immune restoration when it is possible. SUMMARY: Five epidemiologic types of Kaposi are recognized and HHV-8 is associated to all epidemiologic forms of Kaposi. HHV-8 is a virus favoring both angiogenesis and cellular proliferation, which are the two main histological features of Kaposi sarcoma. Although in many cases, treatment of Kaposi sarcoma is not necessary, specific chemotherapy, immunomodulation and immune stimulation are the tools for treating Kaposi sarcoma. Monochemotherapy has been shown to be as efficient as polychemotherapy and less toxic. Immune checkpoint inhibitors gave some promising results, which should be confirmed by prospective studies.

The Role of Dendritic Cells in Immune Control and Vaccination against -Herpesviruses.

The two human oncogenic -herpesviruses, Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV), are prototypic pathogens that are controlled by T cell responses. Despite their ubiquitous distribution, persistent infections and transforming potential, most carriers' immune systems control them for life. Therefore, they serve as paradigms of how near-perfect cell-mediated immune control can be initiated and maintained for decades. Interestingly, EBV especially quite efficiently avoids dendritic cell (DC) activation, and little evidence exists that these most potent antigen-presenting cells of the human body are involved in the priming of immune control against this tumor virus. However, DCs can be harnessed therapeutically to expand virus-specific T cells for adoptive transfer therapy of patients with virus-associated malignancies and are also currently explored for vaccinations. Unfortunately, despite 55 and 25 years of research on EBV and KSHV, respectively, the priming of their immune control that belongs to the most robust and durable immune responses in humans still remains unclear.

[Treatment of acute viral feline upper respiratory tract infections]. / Therapie des akuten viralen Katzenschnupfens.

The main causative agents of feline upper respiratory tract disease (FURTD) are feline herpesvirus-1 (FHV-1) and feline calicivirus (FCV). These viral infections are common, especially in multiple cat households. Severely affected cats often need to be hospitalized. Intensive symptomatic therapy is important in the management of cats with FURTD. The use of antiviral drugs is limited in cats, as they are often ineffective or toxic when given systemically. Antiviral drugs are, therefore, mainly used locally for the treatment of FHV-1-associated eye changes. Famciclovir, however, is an effective drug for systemic therapy in cats with FHV-1-related clinical signs. For FCV, only few antiviral drugs are available. In a controlled study, the use of immunoglobulins in cats with FHV-1 and/or FCV infection reduced clinical signs of FURTD significantly faster.

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.