Major Histocompatibility Complex Class I Allele-specific Cooperative and Competitive Interactions between Immune Evasion Proteins of Cytomegalovirus

Cytomegaloviruses (CMVs) deploy a set of genes for interference with antigen presentation in the major histocompatibility complex (MHC) class I pathway. In murine CMV (MCMV), three genes were identified so far: m04/gp34, m06/gp48, and m152/gp40. While their function as immunoevasins was originally defined after their selective expression, this may not necessarily reflect their biological role during infection. The three immunoevasins might act synergistically, but they might also compete for their common substrate, the MHC class I complexes. To approach this question in a systematic manner, we have generated a complete set of mutant viruses with deletions of the three genes in all seven possible combinations. Surface expression of a set of MHC class I molecules specified by haplotypes H-2d (Kd, Dd, and Ld) and H-2b (Kb and Db) was the parameter for evaluation of the interference with class I trafficking. The data show the following: first, there exists no additional MCMV gene of major influence on MHC class I surface expression; second, the strength of the inhibitory effect of immunoevasins shows an allele-specific hierarchy; and third, the immunoevasins act not only synergistically but can, in certain combinations, interact antagonistically. In essence, this work highlights the importance of studying the immunosubversive mechanisms of cytomegaloviruses in the context of gene expression during the viral replicative cycle in infected cells

Decreased expression of breast cancer resistance protein in the duodenum in patients with obstructive cholestasis

Background/Aims: The expression of transporters involved in bile acid homeostasis is differentially regulated during obstructive cholestasis. Since the drug efflux transporter breast cancer resistance protein (BCRP) is known to transport bile acids, we investigated whether duodenal BCRP expression could be altered during cholestasis. Methods: Using real-time RT-PCR analysis we determined mRNA expression levels in duodenal tissue of 19 cholestatic patients. Expression levels were compared to 14 healthy subjects. BCRP protein staining was determined in biopsies of 6 cholestatic and 6 healthy subjects by immunohistochemistry. Results: We found that in patients with obstructive cholestasis mean duodenal BCRP mRNA levels were significantly reduced to 53% and mean protein staining was reduced to 57%. Conclusions: BCRP, a transporter for bile acids and numerous drugs, appears to be down-regulated in the human duodenum during cholestasis. The clinical impact of these results has to be investigated in further studies. Copyright (c) 2006 S. Karger AG, Basel

Observations of bromine monoxide transport in the Arctic sustained on aerosol particles

The return of sunlight in the polar spring leads to the production of reactive halogen species from the surface snowpack, significantly altering the chemical composition of the Arctic near-surface atmosphere and the fate of long-range transported pollutants, including mercury. Recent work has shown the initial production of reactive bromine at the Arctic surface snowpack; however, we have limited knowledge of the vertical extent of this chemistry, as well as the lifetime and possible transport of reactive bromine aloft. Here, we present bromine monoxide (BrO) and aerosol particle measurements obtained during the March 2012 BRomine Ozone Mercury EXperiment (BROMEX) near Utqiaġvik (Barrow), AK. The airborne differential optical absorption spectroscopy (DOAS) measurements provided an unprecedented level of spatial resolution, over 2 orders of magnitude greater than satellite observations and with vertical resolution unable to be achieved by satellite methods, for BrO in the Arctic. This novel method provided quantitative identification of a BrO plume, between 500 m and 1 km aloft, moving at the speed of the air mass. Concurrent aerosol particle measurements suggest that this lofted reactive bromine plume was transported and maintained at elevated levels through heterogeneous reactions on colocated supermicron aerosol particles, independent of surface snowpack bromine chemistry. This chemical transport mechanism explains the large spatial extents often observed for reactive bromine chemistry, which impacts atmospheric composition and pollutant fate across the Arctic region, beyond areas of initial snowpack halogen production. The possibility of BrO enhancements disconnected from the surface potentially contributes to sustaining BrO in the free troposphere and must also be considered in the interpretation of satellite BrO column observations, particularly in the context of the rapidly changing Arctic sea ice and snowpack

Multi-colour optical monitoring of eight red blazars

We present the observational results of multi-colour optical monitoring of eight red blazars from 2003 September to 2004 February. The aim of our monitoring is to investigate the spectral variability as well as the flux variations at short and long time scales. The observations were carried out using the 1.0 m robotic telescope of Mt. Lemmon Optical Astronomy Observatory, in Arizona, USA, the 0.6 m telescope of Sobaeksan Optical Astronomy Observatory and the 1.8 m telescope of Bohyunsan Optical Astronomy Observatory, in the Republic of Korea. During the observations, all sources show strong flux variations with amplitudes of larger than 0.5 mag. Variations with amplitudes of over 1 mag are found in four sources. Intraday variations with amplitudes larger than 0.15 mag, and a rapid brightness increase with a rate of ~0.2 mag per day in four days, are detected in S5 0716+71. We investigate the relationship between the colour index and source brightness for each source. We find that two out of three FSRQs tend to be redder when they are brighter, and, conversely, all BL Lac objects tend to be bluer. In particular, we find a significant anti-correlation between the V-I colour index and R magnitude for 3C 454.3. This implies that the spectrum became steeper when the source was brighter, which is opposite to the common trend for blazars. In contrast, significant positive correlations are found in 3C 66A, S5 0716+71, and BL Lac. However, there are only very weak correlations for PKS 0735+17 and OJ 287. We propose that the different relative contributions of the thermal versus non-thermal radiation to the optical emission may be responsible for the different trends of the colour index with brightness in FSRQs and BL Lac objects.Comment: 15 pages, 12 figures. Accepted for publication in A&

Locating positions of {\gamma}-ray--emitting regions in blazars

We propose a new method to locate the gamma-ray--emitting positions R_g from the measured time lags T_ob of gamma-ray emission relative to broad emission lines. The method is also applicable to lower frequencies. R_g depends on parameters T_ob, R_BLR, v_d and theta, where R_BLR is the size of broad-line region, v_d is the travelling speed of disturbances down the jet and theta is the viewing angle of the jet axis to the line of sight. As T_ob=0, T_ob<0 or T_ob>0, the broad lines zero-lag, lag or lead the gamma-rays, respectively. It is applied to 3C 273, in which the lines and the radio emission have enough data, but the gamma-rays have not. We find T_ob0 for the 5, 8, 15, 22 and 37 GHz emission relative to the broad lines Ha, Hb and Hg. The lag may be positive or negative, however current data do not allow to discriminate between the two cases. The measured lags are on the order of years. For a given line, T_ob generally decreases as radio frequency increases. This trend most likely results from the radiative cooling of relativistic electrons. The negative lags have an average of T_ob=-2.86 years for the 37 GHz emission, which represents that the lines lag the radio emission. The positive lags have T_ob=3.20 years, which represents that the lines lead the radio emission. We obtain the radio emitting positions R_radio=0.40--2.62 pc and R_radio=9.43--62.31 pc for the negative and positive lags, respectively. From the constraint of R_g </~ R_radio (e.g. Dermer & Schlickeiser 1994; Jorstad et al. 2001), we have R_g </~ 0.40--2.62 pc for the negative lags. For the positive lags, 4.67--30.81<R_g </~ 9.43--62.31 pc. These estimated R_g are consistent with those of other researches. These agreements confirm the reliability of the method and assumptions. The method may be also applicable to BL Lacertae objects, in which broad lines were detected.Comment: 13 pages, 8 figures, MNRAS, acceptanc

Shedding light on the elusive role of endothelial cells in cytomegalovirus dissemination.

Cytomegalovirus (CMV) is frequently transmitted by solid organ transplantation and is associated with graft failure. By forming the boundary between circulation and organ parenchyma, endothelial cells (EC) are suited for bidirectional virus spread from and to the transplant. We applied Cre/loxP-mediated green-fluorescence-tagging of EC-derived murine CMV (MCMV) to quantify the role of infected EC in transplantation-associated CMV dissemination in the mouse model. Both EC- and non-EC-derived virus originating from infected Tie2-cre(+) heart and kidney transplants were readily transmitted to MCMV-naïve recipients by primary viremia. In contrast, when a Tie2-cre(+) transplant was infected by primary viremia in an infected recipient, the recombined EC-derived virus poorly spread to recipient tissues. Similarly, in reverse direction, EC-derived virus from infected Tie2-cre(+) recipient tissues poorly spread to the transplant. These data contradict any privileged role of EC in CMV dissemination and challenge an indiscriminate applicability of the primary and secondary viremia concept of virus dissemination

Optical and radio variability of the BL Lac object AO 0235+16: a possible 5-6 year periodicity

New optical and radio data on the BL Lacertae object AO 0235+16 have been collected in the last four years by a wide international collaboration, which confirm the intense activity of this source. The optical data also include the results of the Whole Earth Blazar Telescope (WEBT) first-light campaign organized in November 1997. The optical spectrum is observed to basically steepen when the source gets fainter. We have investigated the existence of typical variability time scales and of possible correlations between the optical and radio emissions by means of visual inspection, Discrete Correlation Function analysis, and Discrete Fourier Transform technique. The major radio outbursts are found to repeat quasi-regularly with a periodicity of about 5.7 years; this period is also in agreement with the occurrence of some of the major optical outbursts, but not all of them.Comment: to be published in A&

Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response

Natural killer (NK) cells are crucial in resistance to certain viral infections, but the mechanisms used to recognize infected cells remain largely unknown. Here, we show that the activating Ly49P receptor recognizes cells infected with mouse cytomegalovirus (MCMV) by a process that requires the presence of H2-Dk and the MCMV m04 protein. Using H2 chimeras between H2-Db and -Dk, we demonstrate that the H2-Dk peptide-binding platform is required for Ly49P recognition. We identified m04 as a viral component necessary for recognition using a panel of MCMV-deletion mutant viruses and complementation of m04-deletion mutant (Δm04) virus infection. MA/My mice, which express Ly49P and H2-Dk, are resistant to MCMV; however, infection with Δm04 MCMV abrogates resistance. Depletion of NK cells in MA/My mice abrogates their resistance to wild-type MCMV infection, but does not significantly affect viral titers in mice infected with Δm04 virus, implicating NK cells in host protection through m04-dependent recognition. These findings reveal a novel mechanism of major histocompatability complex class I–restricted recognition of virally infected cells by an activating NK cell receptor