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Dive into the research topics where Ali H. Ellebedy is active.

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Featured researches published by Ali H. Ellebedy.


Immunity | 2009

The Intracellular Sensor NLRP3 Mediates Key Innate and Healing Responses to Influenza A Virus via the Regulation of Caspase-1

Paul G. Thomas; Pradyot Dash; Jerry R. Aldridge; Ali H. Ellebedy; Cory Reynolds; Amy J. Funk; William J. Martin; Mohamed Lamkanfi; Richard J. Webby; Kelli L. Boyd; Peter C. Doherty; Thirumala-Devi Kanneganti

Virus-induced interlukin-1beta (IL-1beta) and IL-18 production in macrophages are mediated via caspase-1 pathway. Multiple microbial components, including viral RNA, are thought to trigger assembly of the cryopyrin inflammasome resulting in caspase-1 activation. Here, we demonstrated that Nlrp3(-/-) and Casp1(-/-) mice were more susceptible than wild-type mice after infection with a pathogenic influenza A virus. This enhanced morbidity correlated with decreased neutrophil and monocyte recruitment and reduced cytokine and chemokine production. Despite the effect on innate immunity, cryopyrin-deficiency was not associated with any obvious defect in virus control or on the later emergence of the adaptive response. Early epithelial necrosis was, however, more severe in the infected mutants, with extensive collagen deposition leading to later respiratory compromise. These findings reveal a function of the cryopyrin inflammasome in healing responses. Thus, cryopyrin and caspase-1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.


Current Opinion in Cell Biology | 2011

TOR in the immune system

Koichi Araki; Ali H. Ellebedy; Rafi Ahmed

The target of rapamycin (TOR) is a crucial intracellular regulator of the immune system. Recent studies have suggested that immunosuppression by TOR inhibition may be mediated by modulating differentiation of both effector and regulatory CD4 T cell subsets. However, it was paradoxically shown that inhibiting TOR signaling has immunostimulatory effects on the generation of long-lived memory CD8 T cells. Beneficial effects of TOR inhibition have also been observed with dendritic cells and hematopoietic stem cells. This immune modulation may contribute to lifespan extension seen in mice with mTOR inhibition. Here, we review recent findings on TOR modulation of innate and adaptive immune responses, and discuss potential applications of regulating TOR to provide longer and healthier immunity.


Proceedings of the National Academy of Sciences of the United States of America | 2015

Human Ebola virus infection results in substantial immune activation

Anita K. McElroy; Rama Akondy; Carl W. Davis; Ali H. Ellebedy; Aneesh K. Mehta; Colleen S. Kraft; G. Marshall Lyon; Bruce S. Ribner; Jay B. Varkey; John Sidney; Alessandro Sette; Shelley Campbell; Ute Ströher; Inger K. Damon; Stuart T. Nichol; Christina F. Spiropoulou; Rafi Ahmed

Significance In 2014, Ebola virus became a household term. The ongoing outbreak in West Africa is the largest Ebola virus outbreak ever recorded, with over 20,000 cases and over 8,000 deaths to date. Very little is known about the human cellular immune response to Ebola virus infection, and this lack of knowledge has hindered development of effective therapies and vaccines. In this study, we characterize the human immune response to Ebola virus infection in four patients. We define the kinetics of T- and B-cell activation, and determine which viral proteins are targets of the Ebola virus-specific T-cell response in humans. Four Ebola patients received care at Emory University Hospital, presenting a unique opportunity to examine the cellular immune responses during acute Ebola virus infection. We found striking activation of both B and T cells in all four patients. Plasmablast frequencies were 10–50% of B cells, compared with less than 1% in healthy individuals. Many of these proliferating plasmablasts were IgG-positive, and this finding coincided with the presence of Ebola virus-specific IgG in the serum. Activated CD4 T cells ranged from 5 to 30%, compared with 1–2% in healthy controls. The most pronounced responses were seen in CD8 T cells, with over 50% of the CD8 T cells expressing markers of activation and proliferation. Taken together, these results suggest that all four patients developed robust immune responses during the acute phase of Ebola virus infection, a finding that would not have been predicted based on our current assumptions about the highly immunosuppressive nature of Ebola virus. Also, quite surprisingly, we found sustained immune activation after the virus was cleared from the plasma, observed most strikingly in the persistence of activated CD8 T cells, even 1 mo after the patients’ discharge from the hospital. These results suggest continued antigen stimulation after resolution of the disease. From these convalescent time points, we identified CD4 and CD8 T-cell responses to several Ebola virus proteins, most notably the viral nucleoprotein. Knowledge of the viral proteins targeted by T cells during natural infection should be useful in designing vaccines against Ebola virus.


Proceedings of the National Academy of Sciences of the United States of America | 2014

Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans

Ali H. Ellebedy; Florian Krammer; Gui-Mei Li; Matthew S. Miller; Christopher Chiu; Jens Wrammert; Cathy Y. Chang; Carl W. Davis; Megan McCausland; Rivka Elbein; Srilatha Edupuganti; Paul Spearman; Sarah F. Andrews; Patrick C. Wilson; Adolfo García-Sastre; Mark J. Mulligan; Aneesh K. Mehta; Peter Palese; Rafi Ahmed

Significance Vaccination is the most effective means of attaining protection against influenza viruses. However, the constantly evolving nature of influenza viruses enables them to escape preexisting immune surveillance, and thus thwarts public health efforts to control influenza annual epidemics and occasional pandemics. One solution is to elicit antibodies directed against highly conserved epitopes, such as those within the stem region of influenza HA, the principal target of virus-neutralizing antibody responses. This study shows that annual influenza vaccines induce antibody responses that are largely directed against the highly variable HA head region. In contrast, heterologous immunization with HA derived from influenza strains that are currently not circulating in humans (e.g. H5N1) can substantially increase HA stem-specific responses. The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.


Proceedings of the National Academy of Sciences of the United States of America | 2014

Potential antigenic explanation for atypical H1N1 infections among middle-aged adults during the 2013–2014 influenza season

Susanne L. Linderman; Benjamin S. Chambers; Seth J. Zost; Kaela Parkhouse; Yang Li; Christin Herrmann; Ali H. Ellebedy; Donald M. Carter; Sarah F. Andrews; Nai-Ying Zheng; Min Huang; Yunping Huang; Donna Strauss; Beth H. Shaz; Richard L. Hodinka; Gustavo Reyes-Terán; Ted M. Ross; Patrick C. Wilson; Rafi Ahmed; Jesse D. Bloom; Scott E. Hensley

Significance Influenza viruses typically cause a higher disease burden in children and the elderly, who have weaker immune systems. During the 2013–2014 influenza season, H1N1 viruses caused an unusually high level of disease in middle-aged adults. Here, we show that recent H1N1 strains possess a mutation that allows viruses to avoid immune responses elicited in middle-aged adults. We show that current vaccine strains elicit immune responses that are predicted to be less effective in some middle-aged adults. We suggest that new viral strains should be incorporated into seasonal influenza vaccines so that proper immunity is elicited in all humans, regardless of age and pre-exposure histories. Influenza viruses typically cause the most severe disease in children and elderly individuals. However, H1N1 viruses disproportionately affected middle-aged adults during the 2013–2014 influenza season. Although H1N1 viruses recently acquired several mutations in the hemagglutinin (HA) glycoprotein, classic serological tests used by surveillance laboratories indicate that these mutations do not change antigenic properties of the virus. Here, we show that one of these mutations is located in a region of HA targeted by antibodies elicited in many middle-aged adults. We find that over 42% of individuals born between 1965 and 1979 possess antibodies that recognize this region of HA. Our findings offer a possible antigenic explanation of why middle-aged adults were highly susceptible to H1N1 viruses during the 2013–2014 influenza season. Our data further suggest that a drifted H1N1 strain should be included in future influenza vaccines to potentially reduce morbidity and mortality in this age group.


Proceedings of the National Academy of Sciences of the United States of America | 2011

Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59

Ali H. Ellebedy; Christopher Lupfer; Hazem E. Ghoneim; Jennifer DeBeauchamp; Thirumala-Devi Kanneganti; Richard J. Webby

Clinical studies have indicated that subvirion inactivated vaccines against avian influenza viruses, particularly H5N1, are poorly immunogenic in humans. As a consequence, the use of adjuvants has been championed for the efficient vaccination of a naïve population against avian influenza. Aluminum salts (alum) and the oil-in-water emulsion MF59 are safe and effective adjuvants that are being used with influenza vaccines, but the mechanism underlying their stimulation of the immune system remains poorly understood. It was shown recently that activation of a cytosolic innate immune-sensing complex known as “NLR-Pyrin domain containing 3” (NLRP3) inflammasome, also known as “cryopyrin,” “cold-induced autoinflammatory syndrome 1” (CIAS1), or nacht domain-, leucine-rich repeat-, and PYD-containing protein 3 (Nalp3), is essential for the adjuvant effect of alum. Here we show that the inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adapter protein within the NLRP3 inflammasome, is a crucial element in the adjuvant effect of MF59 when combined with H5N1 subunit vaccines. In the absence of ASC, H5-specific IgG antibody responses are significantly reduced, whereas the responses are intact in NLRP3−/− and caspase-1−/− mice. This defect is caused mainly by the failure of antigen-specific B cells to switch from IgM to IgG production. We conclude that ASC plays an inflammasome-independent role in the induction of antigen-specific humoral immunity after vaccination with MF59-adjuvanted influenza vaccines. These findings have important implications for the rational design of next-generation adjuvants.


Proceedings of the National Academy of Sciences of the United States of America | 2010

Puzzling inefficiency of H5N1 influenza vaccines in Egyptian poultry

Jeong-Ki Kim; Ghazi Kayali; David Walker; Heather L. Forrest; Ali H. Ellebedy; Yolanda Griffin; Adam Rubrum; Mahmoud M. Bahgat; Mohamed A. Kutkat; Mohamed Ashraf Ali; Jerry R. Aldridge; Nicholas J. Negovetich; Scott Krauss; Richard J. Webby; Robert G. Webster

In Egypt, efforts to control highly pathogenic H5N1 avian influenza virus in poultry and in humans have failed despite increased biosecurity, quarantine, and vaccination at poultry farms. The ongoing circulation of HP H5N1 avian influenza in Egypt has caused >100 human infections and remains an unresolved threat to veterinary and public health. Here, we describe that the failure of commercially available H5 poultry vaccines in Egypt may be caused in part by the passive transfer of maternal H5N1 antibodies to chicks, inhibiting their immune response to vaccination. We propose that the induction of a protective immune response to H5N1 is suppressed for an extended period in young chickens. This issue, among others, must be resolved and additional steps must be taken before the outbreaks in Egypt can be controlled.


Microbes and Infection | 2011

Immunity to seasonal and pandemic influenza A viruses

Sophie A. Valkenburg; John A. Rutigliano; Ali H. Ellebedy; Peter C. Doherty; Paul G. Thomas; Katherine Kedzierska

The introduction of a new influenza strain into human circulation leads to rapid global spread. This review summarizes innate and adaptive immunity to influenza viruses, with an emphasis on T-cell responses that provide cross-protection between distinct subtypes and strains. We discuss antigenic variation within T-cell immunogenic peptides and our understanding of pre-existing immunity towards the pandemic A(H1N1) 2009 strain.


Vaccine | 2011

Impact of prior seasonal influenza vaccination and infection on pandemic A (H1N1) influenza virus replication in ferrets

Ali H. Ellebedy; Mariette F. Ducatez; S. Duan; Evelyn Stigger-Rosser; Adam Rubrum; Elena A. Govorkova; Robert G. Webster; Richard J. Webby

Early epidemiologic and serologic studies have suggested pre-existing immunity to the pandemic A (H1N1) 2009 influenza virus (H1N1pdm) may be altering its morbidity and mortality in humans. To determine the role that contemporary seasonal H1N1 virus infection or trivalent inactivated vaccine (TIV) might be playing in this immunity we conducted a vaccination-challenge study in ferrets. Vaccination with TIV was unable to alter subsequent morbidity or contact transmission in ferrets following challenge with H1N1pdm. Conversely, prior infection with the contemporary seasonal H1N1 strain altered morbidity, but not transmission, of H1N1pdm despite the detection of only minimal levels of cross reactive antibodies.


The Journal of Infectious Diseases | 2010

Inactivated Seasonal Influenza Vaccines Increase Serum Antibodies to the Neuraminidase of Pandemic Influenza A(H1N1) 2009 Virus in an Age-Dependent Manner

Glendie Marcelin; Hilliary M. Bland; Nicholas J. Negovetich; Matthew Sandbulte; Ali H. Ellebedy; Ashley Webb; Yolanda Griffin; Jennifer DeBeauchamp; Janet E. McElhaney; Richard J. Webby

Levels of preexisting antibodies to the hemagglutinin of pandemic influenza A(H1N1) 2009 (hereafter pandemic H1N1) virus positively correlate with age. The impact of contemporary seasonal influenza vaccines on establishing immunity to other pandemic H1N1 proteins is unknown. We measured serum antibodies to the neuraminidase (NA) of pandemic H1N1 in adults prior to and after vaccination with seasonal trivalent inactivated influenza vaccines. Serum antibodies to pandemic H1N1 NA were observed in all age groups; however, vaccination elevated levels of pandemic H1N1 NA antibodies predominately in elderly individuals (age, ⩾60 years). Therefore, contemporary seasonal vaccines likely contribute to reduction of pandemic H1N1-associated disease in older individuals.

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Richard J. Webby

St. Jude Children's Research Hospital

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Paul G. Thomas

St. Jude Children's Research Hospital

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Anita K. McElroy

Centers for Disease Control and Prevention

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Christina F. Spiropoulou

Centers for Disease Control and Prevention

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Florian Krammer

Icahn School of Medicine at Mount Sinai

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Jennifer DeBeauchamp

St. Jude Children's Research Hospital

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