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Pathogenic Microbiology Commons

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Articles 1 - 30 of 48

Full-Text Articles in Pathogenic Microbiology

Interferon-Induced Transmembrane Protein 3 Blocks Fusion Of Sensitive But Not Resistant Viruses By Partitioning Into Virus-Carrying Endosomes, Krishna C. Suddala, Christine C. Lee, Paul Meraner, Mariana Marin, Ruben M. Markosyan, Tanay M. Desai, Fredric S. Cohen, Abraham L. Brass, Gregory B. Melikyan Jan 2019

Interferon-Induced Transmembrane Protein 3 Blocks Fusion Of Sensitive But Not Resistant Viruses By Partitioning Into Virus-Carrying Endosomes, Krishna C. Suddala, Christine C. Lee, Paul Meraner, Mariana Marin, Ruben M. Markosyan, Tanay M. Desai, Fredric S. Cohen, Abraham L. Brass, Gregory B. Melikyan

Open Access Articles

Late endosome-resident interferon-induced transmembrane protein 3 (IFITM3) inhibits fusion of diverse viruses, including Influenza A virus (IAV), by a poorly understood mechanism. Despite the broad antiviral activity of IFITM3, viruses like Lassa virus (LASV), are fully resistant to its inhibitory effects. It is currently unclear whether resistance arises from a highly efficient fusion machinery that is capable of overcoming IFITM3 restriction or the ability to enter from cellular sites devoid of this factor. Here, we constructed and validated a functional IFITM3 tagged with EGFP or other fluorescent proteins. This breakthrough allowed live cell imaging of virus co-trafficking and fusion with ...


Cryptococcus Neoformans Cda1 And Its Chitin Deacetylase Activity Are Required For Fungal Pathogenesis, Rajendra Upadhya, Lorina G. Baker, Woei C. Lam, Charles A. Specht, Maureen J. Donlin, Jennifer K. Lodge Nov 2018

Cryptococcus Neoformans Cda1 And Its Chitin Deacetylase Activity Are Required For Fungal Pathogenesis, Rajendra Upadhya, Lorina G. Baker, Woei C. Lam, Charles A. Specht, Maureen J. Donlin, Jennifer K. Lodge

Open Access Articles

Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant of C. neoformans Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model. C. neoformans carries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here ...


Deciphering The Molecular Basis Of Mycobacteria And Lipoglycan Recognition By The C-Type Lectin Dectin-2, Alexiane Decout, Devinder Kaur, Jerome Nigou Nov 2018

Deciphering The Molecular Basis Of Mycobacteria And Lipoglycan Recognition By The C-Type Lectin Dectin-2, Alexiane Decout, Devinder Kaur, Jerome Nigou

Open Access Articles

Dectin-2 is a C-type lectin involved in the recognition of several pathogens such as Aspergillus fumigatus, Candida albicans, Schistosoma mansonii, and Mycobacterium tuberculosis that triggers Th17 immune responses. Identifying pathogen ligands and understanding the molecular basis of their recognition is one of the current challenges. Purified M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) was shown to induce signaling via Dectin-2, an activity that requires the (alpha1 --> 2)-linked mannosides forming the caps. Here, using isogenic M. tuberculosis mutant strains, we demonstrate that ManLAM is a bona fide and actually the sole ligand mediating bacilli recognition by Dectin-2, although M. tuberculosis produces a ...


Select Gp120 V2 Domain Specific Antibodies Derived From Hiv And Siv Infection And Vaccination Inhibit Gp120 Binding To Alpha4beta7, Sakaorat Lertjuthaporn, Shan Lu, Yang Lou, Shixia Wang, James Arthos Aug 2018

Select Gp120 V2 Domain Specific Antibodies Derived From Hiv And Siv Infection And Vaccination Inhibit Gp120 Binding To Alpha4beta7, Sakaorat Lertjuthaporn, Shan Lu, Yang Lou, Shixia Wang, James Arthos

Open Access Articles

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin alpha4beta7, a gut-homing receptor. Using both cell-surface expressed alpha4beta7 and a soluble alpha4beta7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of alpha4beta7 in a cation -sensitive manner and is inhibited ...


Transporters Mrp1 And Mrp2 Regulate Opposing Inflammatory Signals To Control Transepithelial Neutrophil Migration During Streptococcus Pneumoniae Lung Infection, Andrew Zukauskas, Randall J. Mrsny, Paula Cortes Barrantes, Jerrold R. Turner, John M. Leong, Beth A. Mccormick Jul 2018

Transporters Mrp1 And Mrp2 Regulate Opposing Inflammatory Signals To Control Transepithelial Neutrophil Migration During Streptococcus Pneumoniae Lung Infection, Andrew Zukauskas, Randall J. Mrsny, Paula Cortes Barrantes, Jerrold R. Turner, John M. Leong, Beth A. Mccormick

Open Access Articles

Streptococcus pneumoniae remains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we use in vitro biotinylation and neutrophil transmigration and in vivo murine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities ...


The Role Of Eukaryotic Abc-Transporters In Eliciting Neutrophil Infiltration During Streptococcus Pneumoniae Infection, Andrew Zukauskas Jun 2018

The Role Of Eukaryotic Abc-Transporters In Eliciting Neutrophil Infiltration During Streptococcus Pneumoniae Infection, Andrew Zukauskas

GSBS Dissertations and Theses

Streptococcus pneumoniae (S. pneumoniae) is a Gram-positive, encapsulated bacterium capable of causing significant morbidity and mortality throughout the world. A hallmark of S. pneumoniae infection is infiltration of neutrophils (PMNs) that assist in controlling the spread infection but may also contribute to pathology. Paradoxically, studies have shown that limiting PMN infiltration into the lumen of the lung during infection actually betters clinical outcome in experimental S. pneumoniae infection. The final step in PMN luminal trafficking is a Hepoxilin A3 (HXA3)-dependent migration across the pulmonary epithelium. HXA3 is a PMN chemoattractant that forms gradients along the polarized epithelial ...


On The Demographic And Selective Forces Shaping Patterns Of Human Cytomegalovirus Variation Within Hosts, Andrew M. Sackman, Susanne P. Pfeifer, Timothy F. Kowalik, Jeffrey D. Jensen Jan 2018

On The Demographic And Selective Forces Shaping Patterns Of Human Cytomegalovirus Variation Within Hosts, Andrew M. Sackman, Susanne P. Pfeifer, Timothy F. Kowalik, Jeffrey D. Jensen

Open Access Articles

Human cytomegalovirus (HCMV) is a member of the beta -herpesvirus subfamily within Herpesviridae that is nearly ubiquitous in human populations, and infection generally results only in mild symptoms. However, symptoms can be severe in immunonaive individuals, and transplacental congenital infection of HCMV can result in serious neurological sequelae. Recent work has revealed much about the demographic and selective forces shaping the evolution of congenitally transmitted HCMV both on the level of hosts and within host compartments, providing insight into the dynamics of congenital infection, reinfection, and evolution of HCMV with important implications for the development of effective treatments and vaccines.


Heightened Circulating Levels Of Antimicrobial Peptides In Tuberculosis-Diabetes Co-Morbidity And Reversal Upon Treatment, Nathella Pavan Kumar, Kadar Moideen, Vijay Viswanathan, Shanmugam Sivakumar, Pradeep A. Menon, Hardy Kornfeld, Subash Babu Sep 2017

Heightened Circulating Levels Of Antimicrobial Peptides In Tuberculosis-Diabetes Co-Morbidity And Reversal Upon Treatment, Nathella Pavan Kumar, Kadar Moideen, Vijay Viswanathan, Shanmugam Sivakumar, Pradeep A. Menon, Hardy Kornfeld, Subash Babu

Open Access Articles

BACKGROUND: The association of antimicrobial peptides (AMPs) with tuberculosis-diabetes comorbidity (PTB-DM) is not well understood.

METHODS: To study the association of AMPs with PTB-DM, we examined the systemic levels of cathelicidin (LL37), human beta defensin- 2 (HBD2), human neutrophil peptides 1-3, (HNP1-3) and granulysin in individuals with either PTB-DM, PTB, latent TB (LTB) or no TB infection (NTB).

RESULTS: Circulating levels of cathelicidin and HBD2 were significantly higher and granulysin levels were significantly lower in PTB-DM compared to PTB, LTB or NTB, while the levels of HNP1-3 were significantly higher in PTB-DM compared to LTB or NTB individuals. Moreover, the ...


Intestinal Organoids Model Human Responses To Infection By Commensal And Shiga Toxin Producing Escherichia Coli, Sayali S. Karve, Suman Pradhan, Doyle V. Ward, Alison A. Weiss Jun 2017

Intestinal Organoids Model Human Responses To Infection By Commensal And Shiga Toxin Producing Escherichia Coli, Sayali S. Karve, Suman Pradhan, Doyle V. Ward, Alison A. Weiss

Open Access Articles

Infection with Shiga toxin (Stx) producing Escherichia coli O157:H7 can cause the potentially fatal complication hemolytic uremic syndrome, and currently only supportive therapy is available. Lack of suitable animal models has hindered study of this disease. Induced human intestinal organoids (iHIOs), generated by in vitro differentiation of pluripotent stem cells, represent differentiated human intestinal tissue. We show that iHIOs with addition of human neutrophils can model E. coli intestinal infection and innate cellular responses. Commensal and O157:H7 introduced into the iHIO lumen replicated rapidly achieving high numbers. Commensal E. coli did not cause damage, and were completely contained ...


Therapeutic Antibody Against Neisseria Gonorrhoeae Lipooligosaccharide, A Phase-Variable Virulence Factor, Srinjoy Chakraborti May 2017

Therapeutic Antibody Against Neisseria Gonorrhoeae Lipooligosaccharide, A Phase-Variable Virulence Factor, Srinjoy Chakraborti

GSBS Dissertations and Theses

Neisseria gonorrhoeae (Ng) which causes gonorrhea has become multidrug-resistant, necessitating the development of novel therapeutics and vaccines. mAb 2C7 which targets an epitope within an important virulence factor, the lipooligosaccharide (LOS), is a candidate therapeutic mAb. Ninety-four percent of clinical isolates express the 2C7-epitope which is also a vaccine target.

Ng expresses multiple LOS(s) due to phase-variation (pv) of LOS glycosyltransferase (lgt) genes. mAb 2C7 reactivity requires a lactose extension from the LOS core Heptose (Hep) II (i.e. lgtG ‘ON’ [G+]). Pv results in HepI with: two (2-), three (3-), four (4-), or five (5-) hexoses (Hex). How ...


Il-21 Signaling Is Essential For Optimal Host Resistance Against Mycobacterium Tuberculosis Infection, Matthew G. Booty, Palmira Barreira-Silva, Stephen Carpenter, Claudio Nunes-Alves, Miye K. Jacques, Britni L. Stowell, Pushpalatha Jayaraman, Gillian Beamer, Samuel M. Behar Nov 2016

Il-21 Signaling Is Essential For Optimal Host Resistance Against Mycobacterium Tuberculosis Infection, Matthew G. Booty, Palmira Barreira-Silva, Stephen Carpenter, Claudio Nunes-Alves, Miye K. Jacques, Britni L. Stowell, Pushpalatha Jayaraman, Gillian Beamer, Samuel M. Behar

Open Access Articles

IL-21 is produced predominantly by activated CD4+ T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (gammac) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8+ T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4+ and CD8+ T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility ...


Impact Of Microbiota On Resistance To Ocular Pseudomonas Aeruginosa-Induced Keratitis, Abirami Kugadas, Stig Hill Christiansen, Saiprasad Sankaranarayanan, Neeraj K. Surana, Stefanie Gauguet, Ryan Kunz, Raina Fichorova, Thomas Vorup-Jensen, Mihaela Gadjeva Sep 2016

Impact Of Microbiota On Resistance To Ocular Pseudomonas Aeruginosa-Induced Keratitis, Abirami Kugadas, Stig Hill Christiansen, Saiprasad Sankaranarayanan, Neeraj K. Surana, Stefanie Gauguet, Ryan Kunz, Raina Fichorova, Thomas Vorup-Jensen, Mihaela Gadjeva

Pediatric Publications and Presentations

The existence of the ocular microbiota has been reported but functional analyses to evaluate its significance in regulating ocular immunity are currently lacking. We compared the relative contribution of eye and gut commensals in regulating the ocular susceptibility to Pseudomonas aeruginosa-induced keratitis. We find that in health, the presence of microbiota strengthened the ocular innate immune barrier by significantly increasing the concentrations of immune effectors in the tear film, including secretory IgA and complement proteins. Consistent with this view, Swiss Webster (SW) mice that are typically resistant to P. aeruginosa-induced keratitis become susceptible due to the lack of microbiota. This ...


Surveillance Immunity: An Emerging Paradigm Of Innate Defense Activation In Caenorhabditis Elegans, Read Pukkila-Worley Sep 2016

Surveillance Immunity: An Emerging Paradigm Of Innate Defense Activation In Caenorhabditis Elegans, Read Pukkila-Worley

Open Access Articles

No abstract provided.


Plague And The Defeat Of Mammalian Innate Immunity: Systematic Genetic Analysis Of Yersinia Pestis Virulence Factors: A Dissertation, Samantha G. Palace Jul 2016

Plague And The Defeat Of Mammalian Innate Immunity: Systematic Genetic Analysis Of Yersinia Pestis Virulence Factors: A Dissertation, Samantha G. Palace

GSBS Dissertations and Theses

Yersinia pestis, the causative agent of plague, specializes in causing dense bacteremia following intradermal deposition of a small number of bacteria by the bite of an infected flea. This robust invasiveness requires the ability to evade containment by the innate immune system. Of the various mechanisms employed by Y. pestis to subvert the innate immune response and to proliferate rapidly in mammalian tissue, only a few are well-characterized. Here, I present two complementary genetic analyses of Y. pestis adaptations to the mammalian environment. In the first, genome-wide fitness profiling for Y. pestis by Tn-seq demonstrates that the bacterium has adapted ...


Memory Cd8+ T Cell Function During Mycobacterium Tuberculosis Infection: A Dissertation, Stephen M. Carpenter Jun 2016

Memory Cd8+ T Cell Function During Mycobacterium Tuberculosis Infection: A Dissertation, Stephen M. Carpenter

GSBS Dissertations and Theses

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the ...


Identification Of Zika Virus And Dengue Virus Dependency Factors Using Functional Genomics, George Savidis, William M. Mcdougall, Paul Meraner, Jill Perreira, Jocelyn M. Portmann, Gaia Trincucci, Sinu P. John, Aaron M. Aker, Nicholas Renzette, Douglas R. Robbins, Zhiru Guo, Sharone Green, Timothy F. Kowalik, Abraham L. Brass Jun 2016

Identification Of Zika Virus And Dengue Virus Dependency Factors Using Functional Genomics, George Savidis, William M. Mcdougall, Paul Meraner, Jill Perreira, Jocelyn M. Portmann, Gaia Trincucci, Sinu P. John, Aaron M. Aker, Nicholas Renzette, Douglas R. Robbins, Zhiru Guo, Sharone Green, Timothy F. Kowalik, Abraham L. Brass

Microbiology and Physiological Systems Publications and Presentations

The flaviviruses dengue virus (DENV) and Zika virus (ZIKV) are severe health threats with rapidly expanding ranges. To identify the host cell dependencies of DENV and ZIKV, we completed orthologous functional genomic screens using RNAi and CRISPR/Cas9 approaches. The screens recovered the ZIKV entry factor AXL as well as multiple host factors involved in endocytosis (RAB5C and RABGEF), heparin sulfation (NDST1 and EXT1), and transmembrane protein processing and maturation, including the endoplasmic reticulum membrane complex (EMC). We find that both flaviviruses require the EMC for their early stages of infection. Together, these studies generate a high-confidence, systems-wide view of ...


The Ifitms Inhibit Zika Virus Replication, George Savidis, Jill Perreira, Jocelyn M. Portmann, Paul Meraner, Zhiru Guo, Sharone Green, Abraham L. Brass Jun 2016

The Ifitms Inhibit Zika Virus Replication, George Savidis, Jill Perreira, Jocelyn M. Portmann, Paul Meraner, Zhiru Guo, Sharone Green, Abraham L. Brass

Microbiology and Physiological Systems Publications and Presentations

Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.


Leishmania Amazonensis Engages Cd36 To Drive Parasitophorous Vacuole Maturation, Kendi Okuda, Mei Tong, Brian Dempsey, Kathryn J. Moore, Ricardo T. Gazzinelli, Neal S. Silverman Jun 2016

Leishmania Amazonensis Engages Cd36 To Drive Parasitophorous Vacuole Maturation, Kendi Okuda, Mei Tong, Brian Dempsey, Kathryn J. Moore, Ricardo T. Gazzinelli, Neal S. Silverman

Open Access Articles

Leishmania amastigotes manipulate the activity of macrophages to favor their own success. However, very little is known about the role of innate recognition and signaling triggered by amastigotes in this host-parasite interaction. In this work we developed a new infection model in adult Drosophila to take advantage of its superior genetic resources to identify novel host factors limiting Leishmania amazonensis infection. The model is based on the capacity of macrophage-like cells, plasmatocytes, to phagocytose and control the proliferation of parasites injected into adult flies. Using this model, we screened a collection of RNAi-expressing flies for anti-Leishmania defense factors. Notably, we ...


Xct Increases Tuberculosis Susceptibility By Regulating Antimicrobial Function And Inflammation, Yi Cai, Subhalaxmi Nambi, Christopher M. Sassetti, Fudi Wang, Xinchun Chen Apr 2016

Xct Increases Tuberculosis Susceptibility By Regulating Antimicrobial Function And Inflammation, Yi Cai, Subhalaxmi Nambi, Christopher M. Sassetti, Fudi Wang, Xinchun Chen

Open Access Articles

The physiological functions of macrophage, which plays a central role in the pathogenesis of tuberculosis, depend on its redox state. System xc-, a cystine-glutamate transporter, which consists of xCT and CD98, influences many ROS-dependent pathways by regulating the production of the antioxidant glutathione. xCT's ability to alter this critical host redox balance by increasing the glutathione synthesis aspect of phagocyte physiology suggested that it might influence tuberculosis pathogenesis. In this study, we found that the xCT expression was increased in peripheral blood monocyte of active tuberculosis. xCT expression in macrophage was induced by Mycobacterium tuberculosis (Mtb) through TLR2/Akt- ...


Defining The Binding Region In Factor H To Develop A Therapeutic Factor H-Fc Fusion Protein Against Non-Typeable Haemophilus Influenzae, Sandy M. Wong, Jutamas Shaughnessy, Sanjay Ram, Brian J. Akerley Apr 2016

Defining The Binding Region In Factor H To Develop A Therapeutic Factor H-Fc Fusion Protein Against Non-Typeable Haemophilus Influenzae, Sandy M. Wong, Jutamas Shaughnessy, Sanjay Ram, Brian J. Akerley

Open Access Articles

Non-typeable Haemophilus influenzae (NTHi) cause a range of illnesses including otitis media, sinusitis, and exacerbation of chronic obstructive pulmonary disease, infections that contribute to the problem of antibiotic resistance and are themselves often intractable to standard antibiotic treatment regimens. We investigated a strategy to exploit binding of the complement inhibitor Factor H (FH) to NTHi as a functional target for an immunotherapeutic containing the NTHi binding domain of FH fused to the Fc domain of IgG1. Chimeric proteins containing the regions that most FH-binding bacteria use to engage human FH, domains 6 and 7 (FH6,7/Fc) and/or 18 ...


Metagenomic Sequencing With Strain-Level Resolution Implicates Uropathogenic E. Coli In Necrotizing Enterocolitis And Mortality In Preterm Infants, Doyle V. Ward, Matthias Scholz, Moreno Zolfo, Diana H. Taft, Kurt R. Schibler, Adrian Tett, Nicola Segata, Ardythe L. Morrow Mar 2016

Metagenomic Sequencing With Strain-Level Resolution Implicates Uropathogenic E. Coli In Necrotizing Enterocolitis And Mortality In Preterm Infants, Doyle V. Ward, Matthias Scholz, Moreno Zolfo, Diana H. Taft, Kurt R. Schibler, Adrian Tett, Nicola Segata, Ardythe L. Morrow

Open Access Articles

Necrotizing enterocolitis (NEC) afflicts approximately 10% of extremely preterm infants with high fatality. Inappropriate bacterial colonization with Enterobacteriaceae is implicated, but no specific pathogen has been identified. We identify uropathogenic E. coli (UPEC) colonization as a significant risk factor for the development of NEC and subsequent mortality. We describe a large-scale deep shotgun metagenomic sequence analysis of the early intestinal microbiome of 144 preterm and 22 term infants. Using a pan-genomic approach to functionally subtype the E. coli, we identify genes associated with NEC and mortality that indicate colonization by UPEC. Metagenomic multilocus sequence typing analysis further defined NEC-associated strains ...


Tim3 Mediates T Cell Exhaustion During Mycobacterium Tuberculosis Infection, Pushpalatha Jayaraman, Miye K. Jacques, Chen Zhu, Katherine Steblenko, Britni L. Stowell, Asaf Madi, Ana C. Anderson, Vijay K. Kuchroo, Samuel M. Behar Mar 2016

Tim3 Mediates T Cell Exhaustion During Mycobacterium Tuberculosis Infection, Pushpalatha Jayaraman, Miye K. Jacques, Chen Zhu, Katherine Steblenko, Britni L. Stowell, Asaf Madi, Ana C. Anderson, Vijay K. Kuchroo, Samuel M. Behar

Open Access Articles

While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain-containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF ...


Eosinophils As Drivers Of The Il-23/Il-17 Axis: Implications For Acute Aspergillosis And Allergic Asthma: A Dissertation, Evelyn V. Santos Guerra Feb 2016

Eosinophils As Drivers Of The Il-23/Il-17 Axis: Implications For Acute Aspergillosis And Allergic Asthma: A Dissertation, Evelyn V. Santos Guerra

GSBS Dissertations and Theses

Aspergillus fumigatus is an opportunistic fungal pathogen that causes lethal invasive pulmonary disease in immunocompromised hosts and allergic asthma in sensitized individuals. This dissertation explores how eosinophils may protect hosts from acute infection while driving asthma pathogenesis by co-producing IL-23 and IL-17 in both contexts. In an acute model of pulmonary aspergillosis, eosinophils were observed to associate with and kill A. fumigatus spores in vivo. In addition, eosinopenia was correlated with higher mortality rates, decreased recruitment of inflammatory monocytes to the lungs, and decreased expansion of lung macrophages. As IL-17 signaling must occur on a local level to elicit its ...


A Higher Activation Threshold Of Memory Cd8+ T Cells Has A Fitness Cost That Is Modified By Tcr Affinity During Tuberculosis, Stephen M. Carpenter, Claudio Nunes-Alves, Matthew G. Booty, Sing Sing Way, Samuel M. Behar Jan 2016

A Higher Activation Threshold Of Memory Cd8+ T Cells Has A Fitness Cost That Is Modified By Tcr Affinity During Tuberculosis, Stephen M. Carpenter, Claudio Nunes-Alves, Matthew G. Booty, Sing Sing Way, Samuel M. Behar

Microbiology and Physiological Systems Publications and Presentations

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the ...


Protection Against Experimental Cryptococcosis Following Vaccination With Glucan Particles Containing Cryptococcus Alkaline Extracts, Charles A. Specht, Chrono K. Lee, Haibin Huang, Donald J. Tipper, Zu T. Shen, Jennifer K. Lodge, John D. Leszyk, Gary R. Ostroff, Stuart M. Levitz Dec 2015

Protection Against Experimental Cryptococcosis Following Vaccination With Glucan Particles Containing Cryptococcus Alkaline Extracts, Charles A. Specht, Chrono K. Lee, Haibin Huang, Donald J. Tipper, Zu T. Shen, Jennifer K. Lodge, John D. Leszyk, Gary R. Ostroff, Stuart M. Levitz

Infectious Diseases and Immunology Publications and Presentations

A vaccine capable of protecting at-risk persons against infections due to Cryptococcus neoformans and Cryptococcus gattii could reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purified Saccharomyces cerevisiae cell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent ...


Data From: A Higher Activation Threshold Of Memory Cd8+ T Cells Has A Fitness Cost That Is Modified By Tcr Affinity During Tuberculosis, Stephen M. Carpenter, Claudio Nunes-Alves, Matthew G. Booty, Sing Sing Way, Samuel M. Behar Dec 2015

Data From: A Higher Activation Threshold Of Memory Cd8+ T Cells Has A Fitness Cost That Is Modified By Tcr Affinity During Tuberculosis, Stephen M. Carpenter, Claudio Nunes-Alves, Matthew G. Booty, Sing Sing Way, Samuel M. Behar

MaPS Research Data

Manuscript abstract: T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response ...


Utilizing Cmp-Sialic Acid Analogs To Unravel Neisseria Gonorrhoeae Lipooligosaccharide-Mediated Complement Resistance And Design Novel Therapeutics, Sunita Gulati, Ian C. Schoenhofen, Dennis M. Whitfield, Andrew D. Cox, Jianjun Li, Frank St Michael, Evgeny V. Vinogradov, Jacek Stupak, Bo Zheng, Makoto Ohnishi, Magnus Unemo, Lisa A. Lewis, Rachel E. Taylor, Corinna S. Landig, Sandra Diaz, George W. Reed, Ajit Varki, Peter A. Rice, Sanjay Ram Dec 2015

Utilizing Cmp-Sialic Acid Analogs To Unravel Neisseria Gonorrhoeae Lipooligosaccharide-Mediated Complement Resistance And Design Novel Therapeutics, Sunita Gulati, Ian C. Schoenhofen, Dennis M. Whitfield, Andrew D. Cox, Jianjun Li, Frank St Michael, Evgeny V. Vinogradov, Jacek Stupak, Bo Zheng, Makoto Ohnishi, Magnus Unemo, Lisa A. Lewis, Rachel E. Taylor, Corinna S. Landig, Sandra Diaz, George W. Reed, Ajit Varki, Peter A. Rice, Sanjay Ram

Open Access Articles

Neisseria gonorrhoeae deploys a novel immune evasion strategy wherein the lacto-N-neotetraose (LNnT) structure of lipooligosaccharide (LOS) is capped by the bacterial sialyltransferase, using host cytidine-5'-monophosphate (CMP)-activated forms of the nine-carbon nonulosonate (NulO) sugar N-acetyl-neuraminic acid (Neu5Ac), a sialic acid (Sia) abundant in humans. This allows evasion of complement-mediated killing by recruiting factor H (FH), an inhibitor of the alternative complement pathway, and by limiting classical pathway activation ("serum-resistance"). We utilized CMP salts of six additional natural or synthetic NulOs, Neu5Gc, Neu5Gc8Me, Neu5Ac9Ac, Neu5Ac9Az, legionaminic acid (Leg5Ac7Ac) and pseudaminic acid (Pse5Ac7Ac), to define structural requirements of Sia-mediated serum-resistance. While ...


Dna-Containing Immunocomplexes Promote Inflammasome Assembly And Release Of Pyrogenic Cytokines By Cd14+ Cd16+ Cd64high Cd32low Inflammatory Monocytes From Malaria Patients, Isabella C. Hirako, Carolina Gallego-Marin, Marco A. Ataide Oswalso Cruz Founda, Warrison A. Andrade, Humberto Gravina, Bruno C. Rocha, Rosane B. De Oliveira, Dhelio B. Pereira, Joseph Vinetz, Betty Diamond, Sanjay Ram, Douglas T. Golenbock, Ricardo T. Gazzinelli Nov 2015

Dna-Containing Immunocomplexes Promote Inflammasome Assembly And Release Of Pyrogenic Cytokines By Cd14+ Cd16+ Cd64high Cd32low Inflammatory Monocytes From Malaria Patients, Isabella C. Hirako, Carolina Gallego-Marin, Marco A. Ataide Oswalso Cruz Founda, Warrison A. Andrade, Humberto Gravina, Bruno C. Rocha, Rosane B. De Oliveira, Dhelio B. Pereira, Joseph Vinetz, Betty Diamond, Sanjay Ram, Douglas T. Golenbock, Ricardo T. Gazzinelli

Open Access Articles

High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-kappaB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcgammaRIIIA)(+) CD64 (FcgammaRI)(high) CD32 (FcgammaRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of ...


The Epithelial Transmembrane Protein Perp Is Required For Inflammatory Responses To S. Typhimurium Infection: A Dissertation, Kelly N. Hallstrom Oct 2015

The Epithelial Transmembrane Protein Perp Is Required For Inflammatory Responses To S. Typhimurium Infection: A Dissertation, Kelly N. Hallstrom

GSBS Dissertations and Theses

Salmonella enterica subtype Typhimurium (S. Typhimurium) is one of many non-typhoidal Salmonella enterica strains responsible for over one million cases of salmonellosis in the United States each year. These Salmonella strains are also a leading cause of diarrheal disease in developing countries. Nontyphoidal salmonellosis induces gastrointestinal distress that is characterized histopathologically by an influx of polymorphonuclear leukocytes (PMNs), the non-specific effects of which lead to tissue damage and contribute to diarrhea.

Prior studies from our lab have demonstrated that the type III secreted bacterial effector SipA is a key regulator of PMN influx during S. Typhimurium infection and that its ...


Rnasek Is A V-Atpase-Associated Factor Required For Endocytosis And The Replication Of Rhinovirus, Influenza A Virus, And Dengue Virus, Jill Perreira, Aaron Aker, George Savidis, Christopher R. Chin, William M. Mcdougall, Jocelyn M. Portmann, Paul Meraner, Miles Smith, Motiur Rahman, Richard E. Baker, Annick Gauthier, Michael Franti, Abraham L. Brass Aug 2015

Rnasek Is A V-Atpase-Associated Factor Required For Endocytosis And The Replication Of Rhinovirus, Influenza A Virus, And Dengue Virus, Jill Perreira, Aaron Aker, George Savidis, Christopher R. Chin, William M. Mcdougall, Jocelyn M. Portmann, Paul Meraner, Miles Smith, Motiur Rahman, Richard E. Baker, Annick Gauthier, Michael Franti, Abraham L. Brass

Open Access Articles

Human rhinovirus (HRV) causes upper respiratory infections and asthma exacerbations. We screened multiple orthologous RNAi reagents and identified host proteins that modulate HRV replication. Here, we show that RNASEK, a transmembrane protein, was needed for the replication of HRV, influenza A virus, and dengue virus. RNASEK localizes to the cell surface and endosomal pathway and closely associates with the vacuolar ATPase (V-ATPase) proton pump. RNASEK is required for endocytosis, and its depletion produces enlarged clathrin-coated pits (CCPs) at the cell surface. These enlarged CCPs contain endocytic cargo and are bound by the scissioning GTPase, DNM2. Loss of RNASEK alters the ...