Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here, we describe how IAV infection triggers cellular apoptosis and how this process can be exploited towards the development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here we describe how IAV infection triggers cellular apoptosis, and how this process can be exploited towards development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

BackgroundThe failure of DNA vaccination in humans, in contrast to its efficacy in some species, is unexplained. Observational and interventional experimental evidence suggests that DNA immunogenicity may be prevented by binding of human serum amyloid P component (SAP). SAP is the single normal DNA binding protein in human plasma. The drug (R)-1-[6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, miridesap), developed for treatment of systemic amyloidosis and Alzheimer’s disease, depletes circulating SAP by 95–99%. The proof-of-concept HIV-CORE 003 clinical trial tested whether SAP depletion by CPHPC would enhance the immune response in human volunteers to DNA vaccination delivering the HIVconsv immunogen derived from conserved sub-protein regions of HIV-1.MethodsHuman volunteers received 3 intramuscular immunizations with an experimental DNA vaccine (DDD) expressing HIV-1-derived immunogen HIVconsv, with or without prior depletion of SAP by CPHPC. All subjects were subsequently boosted by simian (chimpanzee) adenovirus (C)- and poxvirus MVA (M)-vectored vaccines delivering the same immunogen. After administration of each vaccine modality, the peak total magnitudes, kinetics, functionality and memory subsets of the T-cell responses to HIVconsv were thoroughly characterized.ResultsNo differences were observed between the CPHPC treated and control groups in any of the multiple quantitative and qualitative parameters of the T-cell responses to HIVconsv, except that after SAP depletion, there was a statistically significantly greater breadth of T-cell specificities, that is the number of recognized epitopes, following the DDDC vaccination.ConclusionsThe protocol used here for SAP depletion by CPHPC prior to DNA vaccination produced only a very modest suggestion of enhanced immunogenicity. Further studies will be required to determine whether SAP depletion might have a practical value in DNA vaccination for other plasmid backbones and/or immunogens.Trial registrationClinicaltrials.gov NCT02425241

BackgroundGranulocyte colony-stimulating factor (G-CSF) can induce regulatory T cells (Tregs) as well as myeloid-derived suppressor cells (MDSCs). Despite the immune modulatory effects of G-CSF, results of G-CSF treatment in systemic lupus erythematosus are still controversial. We therefore investigated whether G-CSF can ameliorate lupus nephritis and studied the underlying mechanisms.MethodsNZB/W F1 female mice were treated with G-CSF or phosphate-buffered saline for 5 consecutive days every week from 24 weeks of age, and were analyzed at 36 weeks of age.ResultsG-CSF treatment decreased proteinuria and serum anti-dsDNA, increased serum complement component 3 (C3), and attenuated renal tissue injury including deposition of IgG and C3. G-CSF treatment also decreased serum levels of BUN and creatinine, and ultimately decreased mortality of NZB/W F1 mice. G-CSF treatment induced expansion of CD4+CD25+Foxp3+ Tregs, with decreased renal infiltration of T cells, B cells, inflammatory granulocytes and monocytes in both kidneys and spleen. G-CSF treatment also decreased expression levels of MCP-1, IL-6, IL-2, and IL-10 in renal tissues as well as serum levels of MCP-1, IL-6, TNF-α, IL-10, and IL-17. When Tregs were depleted by PC61 treatment, G-CSF-mediated protective effects on lupus nephritis were abrogated.ConclusionsG-CSF treatment ameliorated lupus nephritis through the preferential expansion of CD4+CD25+Foxp3+ Tregs. Therefore, G-CSF has a therapeutic potential for lupus nephritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0380-x) contains supplementary material, which is available to authorized users.

Middle East respiratory syndrome coronavirus (MERS-CoV) induces severe aggravating respiratory failure in infected patients, frequently resulting in mechanical ventilation. As limited therapeutic antibody is accumulated in lung tissue following systemic administration, inhalation is newly recognized as an alternative, possibly better, route of therapeutic antibody for pulmonary diseases. The nebulization process, however, generates diverse physiological stresses, and thus, the therapeutic antibody must be resistant to these stresses, remain stable, and form minimal aggregates. We first isolated a MERS-CoV neutralizing antibody that is reactive to the receptor-binding domain (RBD) of spike (S) glycoprotein. To increase stability, we introduced mutations into the complementarity-determining regions (CDRs) of the antibody. In the HCDRs (excluding HCDR3) in this clone, two hydrophobic residues were replaced with Glu, two residues were replaced with Asp, and four residues were replaced with positively charged amino acids. In LCDRs, only two Leu residues were replaced with Val. These modifications successfully generated a clone with significantly greater stability and equivalent reactivity and neutralizing activity following nebulization compared to the original clone. In summary, we generated a MERS-CoV neutralizing human antibody that is reactive to recombinant MERS-CoV S RBD protein for delivery via a pulmonary route by introducing stabilizing mutations into five CDRs.

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AimBET proteins have been shown to regulate gene expression including inflammatory genes.MethodsIn order to investigate the role of the BET proteins in immunoglobulin production we treated the human B-cell line CLNH11.4 and primary human B cells and ozone-exposed mice with BET inhibitors (JQ1 or IBET151).ResultsBoth proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription. In vivo treatment of ozone-exposed mice with the BET inhibitor IBET151 similarly inhibited ozone-induced immunoglobulin production. JQ1 did not reduce the protein levels of Brd4 or Oct2 per se but reduced the ability of Brd4 and Oct2 to co-immunoprecipitate and of Oct2 to bind to immunoglobulin gene promoters.ConclusionOur results indicate that BET proteins including Brd4 play a crucial role regulation B-cell-specific gene expression and immunoglobulin production.

The objective of this study was to determine the optimal blade size and timing to transplant seed-stock of Ecklonia cava Kjellman onto the reef structure. We used the modified artificial stepped reef structure. A total of 14 units (3.0 m length × 3.5 m width × 1.1 m height) were deployed 7-8 m deep under the water to examine the optimal blade size and timing to transplant seed-stock of E. cava onto the structures. Sporophytes of E. cava <1 cm in length were all died within 1 month of transplantation. The blades of 5-10 cm in length which were transplanted in March 2007 survived and grew well on the artificial reefs. Growth rates of 5-10 cm size class were higher than those of longer blade sporophytes (20-30 cm size class, transplanted in April) while the survival rates showed no difference between the classes of blade size. Both classes of 5-10 and 20-30 cm in length grew until July, and a reduction in size had occurred in September. These results indicate the importance of the blade size of E. cava and timing for successful transplantation of the seaweed on artificial reef structures.Key Words: artificial reef; barren grounds; Ecklonia cava; seed-stock; transplantation INTRODUCTIONBarren grounds are currently being expanded by destruction of seaweed habitats due to over harvesting, increases in herbivory (e.g., sea urchin and abalone) and sea temperature, and industrial pollution (Serisawa and Ohno 1995, Serisawa et al. 2002, 2003. The situations could lead to a decline in the fisheries of the country (Kim et al. 2006(Kim et al. , 2007(Kim et al. , 2010. It has been observed that both the diversity and biomass of seaweed species are declining in the coastal waters of Korea due to increasing occurrences in whitening event, changes in the oceanic conditions and increased number of grazers. Impacts of the expanded barren fields are particularly serious in waters off Jeju Island and the south and east coasts of the Korean peninsula (Choi et al. 2009, Kang 2010, Kim et al. 2012 -61-280-4750, Fax: +82-61-285-1949 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. . These transplants successfully grew on the artificial reefs and even produced sporelings on the reef and adjacent rocky substrata. However, these artificial reefs (3.0 m length × 3.5 m width × 1.1 m height and a weight of 4.6 tons) (Kim et al. 2012) were affected by grazing invertebrates, such as sea urchins (Strongylocentrotus nudus, S. intermedius, Hemicentrotus pulcherrimus), and mollusks (Chlorostoma turbinate, Haliotis gigantea). In the present study, modified artificial reefs were developed to overcome this grazing issue. The objective of this study was to determine the optimal plant size and timing for transplantation of E. cava seed-stock using the modified artificial stepped reef structure. MA...