All Events

Seminar
Tuesday, February 19, 2019   |   through Tuesday, February 19, 2019   |   4pm   |   SLU   |   Speaker: Mary O'Riordan, PhD   |   Host: Dr Woodward

Cellular stress pathways sense cell dysfunction and govern adaptive responses.  We find that endoplasmic reticulum and mitochondrial stress responses are engaged during macrophage infection by bacterial pathogens, amplifying pro-inflammatory output and antimicrobial effector function.  Upon infection by methicillin-resistant Staphylococcus aureus, the IRE1 ER stress sensor programs mitochondria to increase production of reactive oxygen species, and generation of mitochondria-derived vesicles (MDV).  These MDV are delivered to the bacteria-containing compartment resulting in an accumulation of antimicrobial ROS in the macrophage phagosome.  IRE1 is also critical for neutrophil antimicrobial effector functions, controlling inflammasome activation and NETosis.  Taken together, these results establish a critical role for cellular stress mechanisms in shaping innate immune responses to bacterial infection.

Journal Club
Friday, February 22, 2019   |   through Friday, February 22, 2019   |   9:30-10:30am   |   SLU
Seminar
Tuesday, February 26, 2019   |   through Tuesday, February 26, 2019   |   4pm   |   SLU   |   Speaker: Aimee Shen, PhD   |   Host: Dr Michelle Reniere

The major nosocomial pathogen Clostridium difficile depends on spore germination to initiate infection.  Interestingly, C. difficile’s germinant sensing mechanism has no precedence in other spore-forming bacteria, since it uses bile salts to induce germination and lacks the transmembrane germinant receptors conserved in almost all spore-forming organisms. Instead, C. difficile is thought to use CspC, a soluble pseudoprotease, to sense these unique bile salt germinants. By solving the crystal structure of C. difficile CspC, we identified mutations that alter C. difficile’s ability to sense bile salt germinants as well as different classes of co-germinants. The impact of these findings on our understanding of the mechanism of germinant sensing will be discussed. The second part of the talk will focus on our recent analyses of the role of DNA methylation in epigenetically regulating C. difficile’s physiology in a collaborative project with Dr. Gang Fang at Mt. Sinai and Dr. Rita Tamayo at UNC.

Journal Club
Friday, March 1, 2019   |   through Friday, March 1, 2019   |   9:30-10:30am   |   HSB
Seminar
Tuesday, March 5, 2019   |   through Tuesday, March 5, 2019   |   4pm   |   SLU   |   Speaker: Bill Sugden, PhD   |   Host: Dr Adam Geballe

The genomes of both Epstein-Barr Virus (EBV) and Kaposi's Sarcoma Herpesvirus (KSHV) persist in tumors as plasmids.  We have used live-cell imaging to visualize the synthesis and partitioning of these tumor viral genomes and found they have striking differences that distinguish them as well as features they share. EBV is partitioned quasi-faithfully while KSHV is partitioned randomly. Both viruses have defects in their DNA synthesis so that only 85-90% of their genomes are duplicated each cell cycle. This latter finding means that each virus must provide its host cell one or more selective advantages to be maintained in proliferating cells so that the daughter cells that retain the viral genomes outgrow those that lose them. We have identified some of the advantages EBV provides it associated tumor cells. One type of tumor, pleural effusion lymphomas (PEL), maintains both KSHV in all cases and EBV in about 90% of them. Understanding how PELs develop has been impaired by the difficulty of infecting B cells with KSHV in vitro, and the inability of KSHV to transform them. We have developed an approach to infect peripheral human B cells with KSHV and EBV so that cells are dually infected for the long-term. Some of these cells share multiple features of bona fide PEL cells and are thus transformed. This in vitro transformation of peripheral B-cells by KSHV and EBV will now allow a mechanistic analysis of the viral and cellular genes that mediate early events in the progression towards PEL

Journal Club
Friday, March 8, 2019   |   through Friday, March 8, 2019   |   9:30-10:30am   |   SLU
Seminar
Tuesday, March 12, 2019   |   through Tuesday, March 12, 2019   |   4pm   |   SLU   |   Speaker: Ken Cadwell, PhD   |   Host: Dr Jason Smith

The gut microbiota promotes the development of the immune system and defends against opportunistic infections, but is also implicated in the pathophysiology of many inflammatory disorders. For this reason, a large-scale effort is underway to elucidate how the trillions of bacteria in the intestine evoke beneficial and adverse responses from the host. However, the gastrointestinal tract also harbors other types of infectious agents including viruses and helminths. How these diverse infectious entities interact with the bacterial microbiota and the host is less clear. We found that murine norovirus (MNV), an RNA virus that can establish persist infection of the gut, promotes the development of the intestinal immune system and protects against injury in a manner similar to bacterial members of the microbiota. In contrast, MNV triggers disease pathologies in mice with a mutation Atg16L1, an autophagy gene associated with susceptibility to inflammatory bowel disease (IBD). Therefore, like certain bacterial members of the gut microbiota, MNV can be beneficial, but induces disease in a genetically susceptible host. In another model of IBD, we found that helminth infection reverses disease in Nod2 mutant mice by altering the composition of the bacterial microbiota. We further showed that helminth infection in humans is associated with similar changes in the microbiota composition, revealing a conserved interaction between parasitic worms and intestinal bacteria. These observations are consistent with some versions of the ‘hygiene hypothesis’ suggesting that the increase in the incidence of inflammatory diseases is due to altered exposure to certain infectious agents. We will present our progress in characterizing these transkingdom interactions, and discuss our efforts to improve the animal model for investigating the effect of infectious exposure on inflammatory diseases.

 

Journal Club
Friday, March 15, 2019   |   through Friday, March 15, 2019   |   9:30-10:30am   |   HSB
Seminar
Tuesday, March 19, 2019   |   through Tuesday, March 19, 2019   |   4pm   |   SLU   |   Speaker: Paul Ahlquist, PhD   |   Host: Dr Jenny Hyde

Positive-strand RNA ((+)RNA) viruses replicate their mRNA-sense genomic RNAs on rearranged host membranes, often in 50 - 100 nm vesicular invaginations, a.k.a. spherules.  Our recent cryo-electron microscopy (cryo-EM) of nodavirus spherules provided the first visualization of viral RNAs and proteins in such complexes.  As predicted by our biochemical results, the membrane spherule is filled with coiled filaments consistent with dsRNA replication templates.  Cytoplasmic filaments, likely representing nascent RNA replication products, emerge from the spherule neck apertures. Each spherule neck is surrounded on the cytoplasmic side of the membrane by a striking 12-fold symmetric proteinaceous ring or “crown” that contains multifunctional nodavirus RNA replication protein A.  Our studies of similar bromovirus RNA replication compartments reveal that virus-induced trans-membrane release of oxidation potential activates late RNA replication functions by disulfide bonding of viral replication factors.  These features provide mechanistic insights into RNA replication compartment structure, assembly, function and control. 

Journal Club
Friday, March 22, 2019   |   through Friday, March 22, 2019   |   TBD
Journal Club
Friday, April 5, 2019   |   through Friday, April 5, 2019   |   9:30-10:30am   |   SLU
Journal Club
Friday, April 12, 2019   |   through Friday, April 12, 2019   |   9:30-10:30am   |   HSB
Journal Club
Friday, April 19, 2019   |   through Friday, April 19, 2019   |   9:30-10:30am   |   SLU
Journal Club
Friday, April 26, 2019   |   through Friday, April 26, 2019   |   9:30-10:30am   |   HSB
Journal Club
Friday, May 3, 2019   |   through Friday, May 3, 2019   |   9:30-10:30am   |   SLU
Journal Club
Friday, May 10, 2019   |   through Friday, May 10, 2019   |   9:30-10:30am   |   HSB
Journal Club
Friday, May 17, 2019   |   through Friday, May 17, 2019   |   9:30-10:30am   |   SLU
Departmental Event
Monday, June 3, 2019   |   through Monday, June 3, 2019   |   TBA   |   HUB South Ballroom
Journal Club
Friday, June 14, 2019   |   through Friday, June 14, 2019   |   TBD