SARS coronavirus and innate immunity

The emergence of the highly pathogenic SARS coronavirus (SARS-CoV) has reignited interest in coronavirus biology and pathogenesis. An emerging theme in coronavirus pathogenesis is that the interaction between specific viral genes and the host immune system, specifically the innate immune system, functions as a key determinant in regulating virulence and disease outcomes. Using SARS-CoV as a model, we will review the current knowledge of the interplay between coronavirus infection and the host innate immune system in vivo, and then discuss the mechanisms by which specific gene products antagonize the host innate immune response in cell culture models. Our data suggests that the SARS-CoV uses specific strategies to evade and antagonize the sensing and signaling arms of the interferon pathway. We summarize by identifying future points of consideration that will contribute greatly to our understanding of the molecular mechanisms governing coronavirus pathogenesis and virulence, and the development of severe disease in humans and animals

Future Type Ia Supernova Data as Tests of Dark Energy from Modified Friedmann Equations

In the Cardassian model, dark energy density arises from modifications to the Friedmann equation, which becomes H^2 = g(\rhom), where g(\rhom) is a new function of the energy density. The universe is flat, matter dominated, and accelerating. The distance redshift relation predictions of generalized Cardassian models can be very different from generic quintessence models, and can be differentiated with data from upcoming pencil beam surveys of Type Ia Supernovae such as SNAP. We have found the interesting result that, once $\Omega_m$ is known to 10% accuracy, SNAP will be able to determine the sign of the time dependence of the dark energy density. Knowledge of this sign (which is related to the weak energy condition) will provide a first discrimination between various cosmological models that fit the current observational data (cosmological constant, quintessence, Cardassian expansion). Further, we have performed Monte Carlo simulations to illustrate how well one can reproduce the form of the dark energy density with SNAP. To be concrete we study a class of two parameter ($n$,$q$) generalized Cardassian models that includes the original Cardassian model (parametrized by $n$ only) as a special case. Examples are given of MP Cardassian models that fit current supernovae and CMB data, and prospects for differentiating between MP Cardassian and other models in future data are discussed. We also note that some Cardassian models can satisfy the weak energy condition $w>-1$ even with a dark energy component that has an effective equation of state $w_X < -1$.Comment: revised version accepted by Ap

The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity

BackgroundThe outcome of a viral infection is regulated by complex interactions of viral and host factors. SARS coronavirus (SARS-CoV) engages and regulates several innate immune response pathways during infection. We have previously shown that the SARS-CoV Papain-like Protease (PLpro) inhibits type I interferon (IFN) by inhibiting IRF3 phosphorylation thereby blocking downstream Interferon induction. This finding prompted us to identify other potential mechanisms of inhibition of PLpro on IFN induction.Methods We have used plasmids expressing PLpro and IRF3 including an IRF3 mutant that is constitutively active, called IRF3(5D). In these experiments we utilize transfections, chromatin immunoprecipitation, Electro-mobility Shift Assays (EMSA) and protein localization to identify where IRF3 and IRF3(5D) are inhibited by PLpro.ResultsHere we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response.ConclusionThese results demonstrate an additional mechanism that PLpro is able to inhibit IRF3 signaling. These data suggest novel innate immune antagonism activities of PLpro that may contribute to SARS-CoV pathogenesis

Severe Acute Respiratory Syndrome Coronavirus Evades Antiviral Signaling: Role of nsp1 and Rational Design of an Attenuated Strain

The severe acute respiratory syndrome (SARS) epidemic was caused by the spread of a previously unrecognized infectious agent, the SARS-associated coronavirus (SARS-CoV). Here we show that SARS-CoV could inhibit both virus- and interferon (IFN)-dependent signaling, two key steps of the antiviral response. We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. We engineered an attenuated mutant of nsp1 in SARS-CoV through reverse genetics, and the resulting mutant virus was viable and replicated as efficiently as wild-type virus in cells with a defective IFN response. However, mutant virus replication was strongly attenuated in cells with an intact IFN response. Thus, nsp1 is likely a virulence factor that contributes to pathogenicity by favoring SARS-CoV replication

The continued epidemic threat of SARS-CoV-2 and implications for the future of global public health

A new coronavirus (CoV) called SARS-CoV-2 emerged in Wuhan, China in December 2019 as the etiological agent of a viral pneumonia called COVID-19. The global spread of SARS-CoV-2 has been so extensive that the WHO declared COVID-19 a pandemic on March 11, 2020. Below, we discuss the emergence of SARS-CoV-2 and provide the historical context, which strongly suggests emerging CoVs provide an immediate threat to global public health and will continue to do so in the future

Cardassian Expansion: a Model in which the Universe is Flat, Matter Dominated, and Accelerating

A modification to the Friedmann Robertson Walker equation is proposed in which the universe is flat, matter dominated, and accelerating. An additional term, which contains only matter or radiation (no vacuum contribution), becomes the dominant driver of expansion at a late epoch of the universe. During the epoch when the new term dominates, the universe accelerates; we call this period of acceleration the Cardassian era. The universe can be flat and yet consist of only matter and radiation, and still be compatible with observations. The energy density required to close the universe is much smaller than in a standard cosmology, so that matter can be sufficient to provide a flat geometry. The new term required may arise, e.g., as a consequence of our observable universe living as a 3-dimensional brane in a higher dimensional universe. The Cardassian model survives several observational tests, including the cosmic background radiation, the age of the universe, the cluster baryon fraction, and structure formation.Comment: 12 pages, one eps figure. Accepted by Physics Lett.

Cross-correlation Weak Lensing of SDSS galaxy Clusters II: Cluster Density Profiles and the Mass--Richness Relation

We interpret and model the statistical weak lensing measurements around 130,000 groups and clusters of galaxies in the Sloan Digital Sky Survey presented by Sheldon et al. 2007 (Paper I). We present non-parametric inversions of the 2D shear profiles to the mean 3D cluster density and mass profiles in bins of both optical richness and cluster i-band luminosity. We correct the inferred 3D profiles for systematic effects, including non-linear shear and the fact that cluster halos are not all precisely centered on their brightest galaxies. We also model the measured cluster shear profile as a sum of contributions from the brightest central galaxy, the cluster dark matter halo, and neighboring halos. We infer the relations between mean cluster virial mass and optical richness and luminosity over two orders of magnitude in cluster mass; the virial mass at fixed richness or luminosity is determined with a precision of 13% including both statistical and systematic errors. We also constrain the halo concentration parameter and halo bias as a function of cluster mass; both are in good agreement with predictions of LCDM models. The methods employed here will be applicable to deeper, wide-area optical surveys that aim to constrain the nature of the dark energy, such as the Dark Energy Survey, the Large Synoptic Survey Telescope and space-based surveys

Escape from Human Monoclonal Antibody Neutralization Affects In Vitro and In Vivo Fitness of Severe Acute Respiratory Syndrome Coronavirus

Severe Acute Respiratory Syndrome (SARS) emerged as a human disease in 2002 and detailed phylogenetic analysis and epidemiological studies have suggested that the SARS-Coronavirus (SARS-CoV) originated from animals. The Spike (S) glycoprotein has been identified as a major target of protective immunity and contains at least three regions that are targeted by neutralizing antibodies in the S1 and S2 domains. We previously characterized a panel of neutralizing human monoclonal antibodies (MAbs) but the majority of epitopes recognized by the MAbs remained unknown

Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease

SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

The world was unprepared for coronavirus disease 2019 (COVID-19) and remains ill-equipped for future pandemics. While unprecedented strides have been made developing vaccines and treatments for COVID-19, there remains a need for highly effective and widely available regimens for ambulatory use for novel coronaviruses and other viral pathogens. We posit that a priority is to develop pan-family drug cocktails to enhance potency, limit toxicity, and avoid drug resistance. We urge cocktail development for all viruses with pandemic potential both in the short term (Peer reviewe