Cytomegalovirus-induced immunopathology and its clinical consequences

Human cytomegalovirus (CMV) is a ubiquitous DNA virus that causes severe disease in patients with immature or impaired immune systems. During active infection, CMV modulates host immunity, and CMV-infected patients often develop signs of immune dysfunction, such as immunosuppression and autoimmune phenomena. Furthermore, active viral infection has been observed in several autoimmune diseases, and case reports have linked primary CMV infection and the onset of autoimmune disorders. In addition, CMV infection promotes allograft rejection and graft-versus-host disease in solid organ and bone marrow transplant recipients, respectively, further implicating CMV in the genesis and maintenance of immunopathological phenomena. The mechanisms by which CMV could induce inhibition of host defense, inflammation, and autoimmunity are discussed, as is the treatment of virus-induced immunopathology with antivirals

Experimental and modeling study of drug release from HPMC-based erodible oral thin films

In this work hydroxypropyl methylcellulose (HPMC) fast-dissolving thin films for oral administration are investigated. Furosemide (Class IV of the Biopharmaceutical Classification System) has been used as a model drug for in vitro release tests using three different set-ups: the Franz cell, the millifluidic flow-through device, and the paddle type dissolution apparatus (USP II). In order to enable drug incorporation within HPMC films, a multifunctional excipient, hydroxypropyl- β -cyclodextrin (HP- β -CD) has been included in the formulation, and the influence of HP- β -CD on film swelling, erosion, and release properties has been investigated. Mathematical models capable of describing the swelling and release processes from HPMC erodible thin films in different apparatuses have been developed. In particular, we propose a new model for the description of drug transport and release in a Franz cell that accounts for the effect of the unavoidable imperfect mixing of the receptor chamber

Dengue and falciparum malaria co-infection in travelers returning from Burkina Faso: Report of two cases in Northeastern Italy

Rationale: Malaria and dengue are the most prevalent vector-borne diseases in tropical countries. Plasmodium parasite and dengue virus (DENV) concurrent infection is possible and often under-recognized in geographical areas where these infections are both endemic. Patients concern and diagnosis: We describe the first two cases of Plasmodium falciparum and DENV-3 co-infection in travelers returning to northeastern Italy from Burkina Faso during 2013-2014. Interventions: Malaria infection in both patients was treated with mefloquine. Due to the persistence of symptoms despite of the antimalaria treatment, dengue was also investigated; the treatment of dengue was symptomatic. Outcomes: The patients were discharged in good general condition. Lessons: The need for surveillance of potential malaria and dengue co-infection in travelers returning to Europe from endemic areas is highlighted, as infection with Plasmodium does not exclude arboviral co-infection

In Vitro Reduced Susceptibility to Pentavalent Antimonials of a Leishmania infantum Isolate from a Human Cutaneous Leishmaniasis Case in Central Italy

Cutaneous leishmaniasis (CL) caused by Leishmania (Leishmania) infantum is endemic in the Mediterranean basin. Here we report an autochthonous case of CL in a patient living in central Italy with an unsatisfactory response to treatment with intralesional Meglumine Antimoniate and in vitro demonstration of reduced susceptibility to SbIII. Parasitological diagnosis was first achieved by histopathology on tissue biopsy and the patient was treated with a local infiltration of Meglumine Antimoniate. Since the clinical response at 12 weeks from the treatment’s onset was deemed unsatisfactory, two further skin biopsies were taken for histopathological examination, DNA extraction and parasite isolation. L. (L.) infantum was identified by molecular typing. The low susceptibility to Meglumine Antimoniate was confirmed in vitro: the promastigotes from the patient strain showed significantly lower susceptibility to SbIII (the active trivalent form of antimonial) compared to the reference strain MHOM/TN/80/IPT1. The patient underwent a new treatment course with intravenous liposomal Amphotericin B, reaching complete healing of the lesion. Additional studies are needed to confirm the epidemiological and clinical relevance of reduced susceptibility to SbIII of human L. (L.) infantum isolate in Italy

Adenosine Receptors as Mediators of Both Cell Proliferation and Cell Death of Cultured Human Melanoma Cells

Adenosine displays contradictory effects on cell growth: it improves cell proliferation, but it may also induce apoptosis and impair cell survival. Following the pharmacologic characterization of adenosine receptor expression on the human melanoma cell line A375, we chose A375 as our cellular model to define how the extracellular adenosine signals are conveyed from each receptor. By using selective adenosine receptor agonists or antagonists, we found that A2A stimulation reduced cell viability and cell clone formation, whereas, at the same time, it improved cell proliferation. In support of this finding we demonstrated that the stimulation of A2A adenosine receptors stably expressed in Chinese hamster ovary cell clone reproduced deleterious effects observed in human melanoma cells. A3 stimulation counteracted A2A-induced cell death but also reduced cell proliferation. Furthermore, we found that A3 stimulation ensures cell survival. We demonstrated that adenosine triggers a survival signal via A3 receptor activation and it kills the cell through A2A receptor inducing a signaling pathway that involves protein kinase C and mitogen-activated protein kinases

Rapid communications Ongoing outbreak of visceral leishmaniasis in Bologna

(VL) cases has recently been reported in Bologna Province in northern Italy. Over six months from November 2012 to May 2013, 14 cases occurred, whereas the average number of cases per year was 2.6 (range: 0–8) in 2008 to 2012. VL was diagnosed in a median of 40 days (range: 15–120) from disease onset. This delay in diagnosis shows the need for heightened awareness of clinicians for autochthonous VL in Europe. From November 2012 to May 2013, public health authorities, microbiologists and clinicians in Bologna Province, northern Italy, noted an upsurge in human cases of visceral leishmaniasis. During these six months, 14 cases were notified, an over five-fold increase compared with the annual average of 2.

Interplay between Human Cytomegalovirus and Intrinsic/Innate Host Responses: A Complex Bidirectional Relationship

The interaction between human cytomegalovirus (HCMV) and its host is a complex process that begins with viral attachment and entry into host cells, culminating in the development of a specific adaptive response that clears the acute infection but fails to eradicate HCMV. We review the viral and cellular partners that mediate early host responses to HCMV with regard to the interaction between structural components of virions (viral glycoproteins) and cellular receptors (attachment/entry receptors, toll-like receptors, and other nucleic acid sensors) or intrinsic factors (PML, hDaxx, Sp100, viperin, interferon inducible protein 16), the reactions of innate immune cells (antigen presenting cells and natural killer cells), the numerous mechanisms of viral immunoevasion, and the potential exploitation of events that are associated with early phases of virus-host interplay as a therapeutic strategy

A sex and gender perspective for neglected zoonotic diseases

Sex-driven and gender-driven diversities in health and diseases should be considered to promote equitable and more effective health for all. Nevertheless, these diversities are not sufficiently taken into consideration when approaching diseases, including infectious diseases. Neglected infectious diseases (NIDs) are a group of diseases, more prevalent in - but not limited to - tropical areas, that are almost absent from the global health agenda. NIDs are related to poverty, associated with stigma and social exclusion and prone to perpetuate health inequities from different perspectives including sex and gender. There is consensus that women and men are differently affected by NIDs. Many epidemiological studies have shown that being a man is a risk factor for several infectious diseases; a number of evidences indicate that sex-related hormonal and chromosomal factors contribute to distinct host’s response to infections in males and females. Conversely, women and girls experience a greater share of the NID burden due to their disproportionate poverty, illiteracy, lower education and social status particularly in low- and middle-income countries. More generally, different professional and environmental exposure can also influence dissimilar disease burden in men and women, but these aspects are seldom considered in clinical practice and in epidemiological surveillance. This opinion paper has the objective of describing the role of sex and gender-based differences for the management and control of NIDs with the scope of orientating research, clinical management and public health strategies towards a gender- and sex- balanced approach. Various NIDs will be examined as examples (case studies) to describe the biological features as well as organizational structures in healthcare and cultural aspects that should be considered for a gender-neutral management of these diseases as well as for the development of individualized anti-infectious treatments that take sex-specific host factors into account. An increased focus on sex together with gender diversities in health and health care services for NIDs is crucial to develop personalized and targeted therapeutic approaches but also to maximize the impact of interventions and public health strategies aimed at eliminating some of them by 2030

Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria

The Fulani ethnic group from West Africa is relatively better protected against Plasmodium falciparum malaria as compared to other sympatric ethnic groups, such as the Dogon. However, the mechanisms behind this lower susceptibility to malaria are largely unknown, particularly those concerning innate immunity. Antigen-presenting cells (APCs), and in particular dendritic cells (DCs) are important components of the innate and adaptive immune systems. Therefore, in this study we investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. Lower frequency and increased activation was observed in circulating plasmacytoid DCs and BDCA-3+ myeloid DCs of infected Fulani as compared to their uninfected counterparts. Conversely, a higher frequency and reduced activation was observed in the same DC subsets obtained from peripheral blood of P. falciparum-infected Dogon children as compared to their uninfected peers. Moreover, infected individuals of both ethnic groups exhibited higher percentages of both classical and inflammatory monocytes that were less activated as compared to their non-infected counterparts. In line with APC impairment during malaria infection, TLR4, TLR7 and TLR9 responses were strongly inhibited by P. falciparum infection in Dogon children, while no such TLR inhibition was observed in the Fulani children. Strikingly, the TLR-induced IFN-γ release was completely abolished in the Dogon undergoing infection while no difference was seen within infected and non-infected Fulani. Thus, P. falciparum infection is associated with altered activation status of important APC subsets and strongly inhibited TLR responses in peripheral blood of Dogon children. In contrast, P. falciparum induces DC activation and does not affect the innate response to specific TLR ligands in Fulani children. These findings suggest that DCs and TLR signalling may be of importance for the protective immunity against malaria observed in the Fulani