Commentary on immune system associated diseases caused byviruses: The Role of EBV

In her review using the human Epstein–Barr virus (EBV) as an example, Dr. Chen intends to illustrate how host immune systems have evolved in response to pathogens or in many cases co-evolved with pathogens. She discusses why EBV in most people causes what appears to be a self-limiting lymphoproliferative disease (or is it? See her discussion of autoimmune diseases and EBV), but in a very small proportion of individuals the virus causes malignant diseases of severe consequence. She reviews some of the plausible explanations that may include interactions of environmental and host genetic factors resulting in EBV associated malignancies. She points out that EBV may not merely transform B cells, but it could also impact the host immune system on a much more global basis than previously realized. She also suggests that EBV associated diseases, in lieu of reflecting the pathogenic potential of the virus, are actually a reflection of the genetic predisposition of certain populations to the modulate immune system inappropriately in response to the virus infection. She supports this notion by detailing the abnormal modulation of NKT cells when the host is infected with EBV. For example, she cites a study that shows that the frequencies of regulatory CD8 + NKT, but not CD4 + NKT cells, in EBV associated Burkitt\u27s lymphoma (BL) and nasopharyngeal carcinoma (NPC) patients are much lower than CD8 + NKT levels in healthy EBV carriers (Yuling et al., 2009), concluding that a skewed NKT cell response might modify the pathogenesis caused by the virus. She also supports her supposition that EBV pathogenesis is likely due to improper immune modulation in response to the infection by reviewing the data associating autoimmune diseases with EBV infections, especially focusing on multiple sclerosis (MS). She cites a study by Serafini et al. (2007) in which it was found that that almost 100% of the early onset MS cases with the secondary progressive phase contain dysregulated EBV infected plasma cells in MS brains. She also reviews other studies that describe atypical responses of MS patients who have been exposed to EBV. Nevertheless, the cause and effect link, EBV to MS, is still tenuous, yet intriguing. She concludes that the malignancies associated with EBV infection and especially the autoimmune diseases associated with EBV infection may result from human genetic variations that cause the host to differentially modulate the immune response to EBV infection to the detriment of the host

Animal models for the study of influenza pathogenesis and therapy

Influenza A viruses causes a variety of illnesses in humans. The most common infection, seasonal influenza, is usually a mild, self-limited febrile syndrome, but it can be more severe in infants, the elderly, and immunodeficient persons, in whom it can progress to severe viral pneumonitis or be complicated by bacterial superinfection, leading to pneumonia and sepsis. Seasonal influenza also occasionally results in neurologic complications. Rarely, viruses that have spread from wild birds to domestic poultry can infect humans; such “avian influenza” can range in severity from mild conjunctivitis through the rapidly lethal disease seen in persons infected with the H5N1 virus that first emerged in Hong Kong in 1997. To develop effective therapies for this wide range of diseases, it is essential to have laboratory animal models that replicate the major features of illness in humans. This review describes models currently in use for elucidating influenza pathogenesis and evaluating new therapeutic agents

Protease inhibitors targeting coronavirus and filovirus entry.

In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics

Inhibition of adenovirus serotype 14 infection by octadecyloxyethyl esters of (S)-[(3-hydroxy-2-phosphonomethoxy)propyl]- nucleosides in vitro.

On September 22, 2008, a physician on Prince of Wales Island, Alaska, notified the Alaska Department of Health and Social Services (ADHSS) of an unusually high number of adult patients with recently diagnosed pneumonia (n = 10), including three persons who required hospitalization and one who died. ADHSS and CDC conducted an investigation to determine the cause and distribution of the outbreak, identify risk factors for hospitalization, and implement control measures. This report summarizes the results of that investigation, which found that the outbreak was caused by adenovirus 14 (Ad14), an emerging adenovirus serotype in the United States that is associated with a higher rate of severe illness compared with other adenoviruses. Among the 46 cases identified in the outbreak from September 1 through October 27, 2008, the most frequently observed characteristics included the following: male (70%), Alaska Native (61%), underlying pulmonary disease (44%), aged > or = 65 years (26%), and current smoker (48%). Patients aged > or = 65 years had a fivefold increased risk for hospitalization. The most commonly reported symptoms were cough (100%), shortness of breath (87%), and fever (74%). Of the 11 hospitalized patients, three required intensive care, and one required mechanical ventilation. One death was reported. Ad14 isolates obtained during the outbreak were identical genetically to those in recent community-acquired outbreaks in the United States which suggests the emergence of a new, and possibly more virulent Ad14 variant. Clinicians should consider Ad14 infection in the differential diagnosis for patients with community-acquired pneumonia, particularly when unexplained clusters of severe respiratory infections are detected

Submillimetre and far-infrared spectral energy distributions of galaxies: the luminosity-temperature relation and consequences for photometric redshifts

The spectral energy distributions (SEDs) of dusty high-redshift galaxies are poorly sampled in frequency and spatially unresolved. Their form is crucially important for estimating the large luminosities of these galaxies accurately, for providing circumstantial evidence concerning their power sources, and for estimating their redshifts in the absence of spectroscopic information. We discuss the suite of parameters necessary to describe their SEDs adequately without introducing unnecessary complexity. We compare directly four popular descriptions, explain the key degeneracies between the parameters in each when confronted with data, and highlight the differences in their best-fitting values. Using one representative SED model, we show that fitting to even a large number of radio, submillimetre and far-infrared (far-IR) continuum colours provides almost no power to discriminate between the redshift and dust temperature of an observed galaxy, unless an accurate relationship with a tight scatter exists between luminosity and temperature for the whole galaxy population. We review our knowledge of this luminosity-dust temperature relation derived from three galaxy samples, to better understand the size of these uncertainties. Contrary to recent claims, we stress that far-IR-based photometric redshifts are unlikely to be sufficiently accurate to impose useful constraints on models of galaxy evolution: finding spectroscopic redshifts for distant dusty galaxies will remain essential.Comment: 14 pages, 14 figures, in press at MNRAS. Replaced with final updated proof versio

The non-thermal superbubble in IC 10 : the generation of cosmic ray electrons caught in the act

Superbubbles are crucial for stellar feedback, with supposedly high (of the order of 10 per cent) thermalization rates. We combined multiband radio continuum observations from the Very Large Array (VLA) with Effelsberg data to study the non-thermal superbubble (NSB) in IC 10, a starburst dwarf irregular galaxy in the Local Group. Thermal emission was subtracted using a combination of Balmer Hα and VLA 32 GHz continuum maps. The bubble’s nonthermal spectrum between 1.5 and 8.8 GHz displays curvature and can be well fitted with a standard model of an ageing cosmic ray electron population. With a derived equipartition magnetic field strength of 44 ±8 μG, and measuring the radiation energy density from Spitzer MIPS maps as 5±1×10−11 erg cm−3, we determine, based on the spectral curvature, a spectral age of the bubble of 1.0 ± 0.3 Myr. Analysis of the LITTLE THINGS HI data cube shows an expanding HI hole with 100 pc diameter and a dynamical age of 3.8 ± 0.3 Myr, centred to within 16 pc on IC 10 X-1, a massive stellar mass black hole (M > 23 M⊙). The results are consistent with the expected evolution for a superbubble with a few massive stars, where a very energetic event like a Type Ic supernova/hypernova has taken place about 1 Myr ago. We discuss alternatives to this interpretationPeer reviewe

Coumarins and pyranocoumarins, potential novel pharmacophores for inhibition ofmeasles virus replication

A series of coumarin and pyranocoumarin analogues were evaluated in vitro for antiviral efficacy against measles virus (MV), strain Chicago. Of the 22 compounds tested for inhibition, six were found to have selectivity indices greater than 10. These were compounds 5-hydroxy-7-propionyloxy- 4-propylcoumarin (2a), 5,7-bis(tosyloxy)-4- propylcoumarin (7); 5-hydroxy-4-propyl-7-tosyloxy- coumarin (8); 6,6-dimethyl-9-propionyloxy-4- propyl-2H,6H-benzo[1,2-b:3,4-b′]dipyran-2-one (9); 6,6-dimethyl-9-pivaloyloxy-4-propyl-2H,6Hbenzo[ 1,2-b:3,4-b′]dipyran-2-one (10); and 7,8-cis- 10,11,12-trans-4-propyl-6,6,10,11-tetramethyl- 7,8,9-trihydroxy-2H,6H,12H-benzo[1,2-b:3,4-b′:5,6- b′′]tripyran-2-one (18). Three of the active drugs were propyl coumarin analogues (2a, 7 and 8), two were dipyranone or chromeno-coumarins (9 and 10), and one was a benzotripyranone with a coumarin nucleus (18). Some appeared to be rather specific and potent inhibitors of MV with EC50 values ranging from 0.2 to 50 μg/ml and the majority of the EC50 values being less than 5 μg/ml. The compounds inhibited an additional nine strains of MV, and in virucidal tests the drugs did not physically disrupt the virion to inhibit virus replication. The inhibitory activity for one of the compounds tested (7) was somewhat dependent on virus concentration and it was still active when added to cells up to 24 h after virus exposure. When used in combination with ribavirin, compound 7 appeared not to profoundly affect the antiviral efficacy of ribavirin or its cell-associated toxicity. However, a slightly antagonistic MVinhibitory effect was observed at the highest concentration of ribavirin used in combination with most concentrations of compound 7 tested. This and related compounds may be valuable leads in the development of a potent and selective class of MV inhibitors that could be used in future in the clinic

Inhibition of measles virus replication by 5\u27-Norcarbocyclic nucleoside analogs

Despite intense efforts to increase vaccine coverage, measles virus (MV) still causes significant morbidity and mortality in the world, sometimes as the result of severe, chronic, lethal disease. In an effort to develop therapies to supplement immunization strategies, a number of 5′-nor carbocyclic adenosine analogues were evaluated for anti-MV activity in CV-1 monkey kidney cells. Of those compounds tested, those either unsubstituted at C4 or possessing a hydroxyl, azido or amino substituent at that position were the most active, with particularly significant inhibition of MV, strain Chicago-1. The EC50 values against this strain ranged from100 mg/ml in actively growing and stationary-phase cells. Results suggest that these compounds may be clinically useful anti-MV virus agents

Inducible Bronchus-Associated Lymphoid Tissue Elicited by a Protein Cage Nanoparticle Enhances Protectionin Mice against Diverse Respiratory Viruses

Destruction of the architectural and subsequently the functional integrity of the lung following pulmonary viral infections is attributable to both the extent of pathogen replication and to the host-generated inflammation associated with the recruitment of immune responses. The presence of antigenically disparate pulmonary viruses and the emergence of novel viruses assures the recurrence of lung damage with infection and resolution of each primary viral infection. Thus, there is a need to develop safe broad spectrum immunoprophylactic strategies capable of enhancing protective immune responses in the lung but which limits immune-mediated lung damage. The immunoprophylactic strategy described here utilizes a protein cage nanoparticle (PCN) to significantly accelerate clearance of diverse respiratory viruses after primary infection and also results in a host immune response that causes less lung damage

Efficacy of Combined Therapy with Amantadine, Oseltamivir, and Ribavirin In Vivo against Susceptible and Amantadine-Resistant Influenza A Viruses

The limited efficacy of existing antiviral therapies for influenza – coupled with widespread baseline antiviral resistance – highlights the urgent need for more effective therapy. We describe a triple combination antiviral drug (TCAD) regimen composed of amantadine, oseltamivir, and ribavirin that is highly efficacious at reducing mortality and weight loss in mouse models of influenza infection. TCAD therapy was superior to dual and single drug regimens in mice infected with drug-susceptible, low pathogenic A/H5N1 (A/Duck/MN/1525/81) and amantadine-resistant 2009 A/H1N1 influenza (A/California/04/09). Treatment with TCAD afforded >90% survival in mice infected with both viruses, whereas treatment with dual and single drug regimens resulted in 0% to 60% survival. Importantly, amantadine had no activity as monotherapy against the amantadine-resistant virus, but demonstrated dose-dependent protection in combination with oseltamivir and ribavirin, indicative that amantadine's activity had been restored in the context of TCAD therapy. Furthermore, TCAD therapy provided survival benefit when treatment was delayed until 72 hours post-infection, whereas oseltamivir monotherapy was not protective after 24 hours post-infection. These findings demonstrate in vivo efficacy of TCAD therapy and confirm previous reports of the synergy and broad spectrum activity of TCAD therapy against susceptible and resistant influenza strains in vitro