Christopher Bennett M.D. M.A. is a physician scientist in the Department of Emergency Medicine at Stanford University. He completed residency training at Harvard Medical School's program in Emergency Medicine based at Massachusetts General Hospital. Bennett graduated with honors from Winthrop University (B.S. in Biology), earned a graduate degree from Duke University (M.A. in Genetics and Genomics), and was awarded his medical degree (M.D.) from The University of North Carolina at Chapel Hill, School of Medicine. In addition to his formal graduate training, Bennett was previously a scientist with the Lineberger Comprehensive Cancer Center, a Howard Hughes Medical Institute Fellow at Johns Hopkins’s McKusick-Nathans Institute of Genetic Medicine, and a researcher with the Emergency Medicine Network based at Harvard and Massachusetts General Hospital.
Christopher previously served on the 2018-2019 Board of Directors for the Society for Academic Emergency Medicine (SAEM); after his term on the Board, he was a member of the SAEM executive taskforce on Equity and Inclusion. He was subsequently a founding member of the SAEM Equity and Inclusion Committee, a position he continues to hold. He also served on the Massachusetts Medical Society's 2019-2020 Committee on Publications which directs the publication and distribution of the New England Journal of Medicine. His research has appeared in journals such as the New England Journal of Medicine, JAMA, and JAMA Surgery. His writing has appeared in The American Journal of Bioethics, STAT News, KevinMD.com, and Forbes.
Boards, Advisory Committees, Professional Organizations
Board of Trustees, Society for Academic Emergency Medicine Foundation (2021 - Present)
Residency: Harvard Medical School (2020) MA
Graduate Degree, Duke University, Genetics and Genomics (2011)
Medical Education: University of North Carolina School of Medicine (2016) NC
Multi-Center Study of Outcomes Among Persons with HIV who Presented to US Emergency Departments with suspected SARS-CoV-2.
Journal of acquired immune deficiency syndromes (1999)
BACKGROUND: There is a need to characterize patients with HIV with suspected severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2).SETTING: Multicenter registry of patients from 116 emergency departments in 27 US states.METHODS: Planned secondary analysis of patients with suspected SARS-CoV-2, with (n=415) and without (n=25,306) HIV. Descriptive statistics were used to compare patient information and clinical characteristics by SARS-CoV-2 and HIV status. Unadjusted and multivariable models were used to explore factors associated with death, intubation, and hospital length of stay. Kaplan-Meier curves were used to estimate survival by SARS-CoV-2 and HIV infection status.RESULTS: Patients with both SARS-CoV-2 and HIV and patients with SARS-CoV-2 but without HIV had similar admission rates (62.7% versus 58.6%, p=0.24), hospitalization characteristics (e.g. rates of admission to the intensive care unit from the ED [5.0% versus 6.3%, p=0.45] and intubation [10% versus 13.3%, p=0.17]), and rates of death (13.9% versus 15.1%, p=0.65). They also had a similar cumulative risk of death (log-rank p=0.72). However, patients with both HIV and SARS-CoV-2 infections compared to patients with HIV but without SAR-CoV-2 had worsened outcomes, including increased mortality (13.9% versus 5.1%, p<0.01, log rank p<0.0001) and their deaths occurred sooner (median 11.5 days versus 34 days, p<0.01).CONCLUSION: Among ED patients with HIV, clinical outcomes associated with SARS-CoV-2 infection are not worse when compared to patients without HIV, but SARS-CoV-2 infection increased risk of death in patients with HIV.
View details for DOI 10.1097/QAI.0000000000002795
View details for PubMedID 34483295
Evaluation of the 2020 Pediatric Emergency Physician Workforce in the US.
JAMA network open
2021; 4 (5): e2110084
Importance: Given the mortality disparities among children and adolescents in rural vs urban areas, the unique health care needs of pediatric patients, and the annual emergency department volume for this patient population, understanding the availability of pediatric emergency physicians (EPs) is important. Information regarding the available pediatric EP workforce is limited, however.Objective: To describe the demographic characteristics, training, board certification, and geographic distribution of the 2020 clinically active pediatric EP workforce in the US.Design, Setting, and Participants: This national cross-sectional study of the 2020 pediatric EP workforce used the American Medical Association Physician Masterfile database, which was linked to American Board of Medical Specialties board certification information. Self-reported training data in the database were analyzed to identify clinically active physicians who self-reported pediatric emergency medicine (EM) as their primary or secondary specialty. The Physician Masterfile data were obtained on March 11, 2020.Main Outcomes and Measures: The Physician Masterfile was used to identify all clinically active pediatric EPs in the US. The definition of EM training was completion of an EM program (inclusive of both an EM residency and/or a pediatric EM fellowship) or a combined EM program (internal medicine and EM, family medicine and EM, or pediatrics and EM). Physician location was linked and classified by county-level Urban Influence Codes. Pediatric EP density was calculated and mapped using US Census Bureau population estimates.Results: A total of 2403 clinically active pediatric EPs were working in 2020 (5% of all clinically active emergency physicians), of whom 1357 were women (56%) and the median (interquartile range) age was 46 (40-55) years. The overall pediatric EP population included 1718 physicians (71%) with EM training and 641 (27%) with pediatric training. Overall, 1639 (68%) were board certified in pediatric EM, of whom 1219 (74%) reported EM training and 400 (24%) reported pediatrics training. Nearly all pediatric EPs worked in urban areas (2369 of 2402 [99%]), and pediatric EPs in urban compared with rural areas were younger (median [interquartile range] age, 46 [40-55] years vs 59 [48-65] years). Pediatric EPs who completed their training 20 years ago or more compared with those who completed training more recently were less likely to work in urban settings (633 [97%] vs 0-4 years: 440 [99%], 5-9 years: 547 [99%], or 10-19 years: 723 [99%]; P=.006). Three states had 0 pediatric EPs (Montana, South Dakota, and Wyoming), and 3 states had pediatric EPs in only 1 county (Alaska, New Mexico, and North Dakota). Less than 1% of counties had 4 or more pediatric EPs per 100 000 population.Conclusions and Relevance: This study found that almost all pediatric EPs worked in urban areas, leaving rural areas of the US with limited availability of pediatric emergency care. This finding may have profound implications for children and adolescents needing emergency care.
View details for DOI 10.1001/jamanetworkopen.2021.10084
View details for PubMedID 34003272
Clinical prediction rule for SARS-CoV-2 infection from 116 U.S. emergency departments 2-22-2021.
2021; 16 (3): e0248438
OBJECTIVES: Accurate and reliable criteria to rapidly estimate the probability of infection with the novel coronavirus-2 that causes the severe acute respiratory syndrome (SARS-CoV-2) and associated disease (COVID-19) remain an urgent unmet need, especially in emergency care. The objective was to derive and validate a clinical prediction score for SARS-CoV-2 infection that uses simple criteria widely available at the point of care.METHODS: Data came from the registry data from the national REgistry of suspected COVID-19 in EmeRgency care (RECOVER network) comprising 116 hospitals from 25 states in the US. Clinical variables and 30-day outcomes were abstracted from medical records of 19,850 emergency department (ED) patients tested for SARS-CoV-2. The criterion standard for diagnosis of SARS-CoV-2 required a positive molecular test from a swabbed sample or positive antibody testing within 30 days. The prediction score was derived from a 50% random sample (n = 9,925) using unadjusted analysis of 107 candidate variables as a screening step, followed by stepwise forward logistic regression on 72 variables.RESULTS: Multivariable regression yielded a 13-variable score, which was simplified to a 13-point score: +1 point each for age>50 years, measured temperature>37.5°C, oxygen saturation<95%, Black race, Hispanic or Latino ethnicity, household contact with known or suspected COVID-19, patient reported history of dry cough, anosmia/dysgeusia, myalgias or fever; and -1 point each for White race, no direct contact with infected person, or smoking. In the validation sample (n = 9,975), the probability from logistic regression score produced an area under the receiver operating characteristic curve of 0.80 (95% CI: 0.79-0.81), and this level of accuracy was retained across patients enrolled from the early spring to summer of 2020. In the simplified score, a score of zero produced a sensitivity of 95.6% (94.8-96.3%), specificity of 20.0% (19.0-21.0%), negative likelihood ratio of 0.22 (0.19-0.26). Increasing points on the simplified score predicted higher probability of infection (e.g., >75% probability with +5 or more points).CONCLUSION: Criteria that are available at the point of care can accurately predict the probability of SARS-CoV-2 infection. These criteria could assist with decisions about isolation and testing at high throughput checkpoints.
View details for DOI 10.1371/journal.pone.0248438
View details for PubMedID 33690722
- Proportions of Faculty Self-identifying as Black or African American at US Medical Schools, 1990-2020. JAMA 2021; 326 (7): 671-672
- Female emergency physician workforce in the United States, 2020. The American journal of emergency medicine 2021
Examining Parity among Black and Hispanic Resident Physicians.
Journal of general internal medicine
The US physician workforce does not represent the racial or ethnic diversity of the population it serves.To assess whether the proportion of US physician trainees of Black race and Hispanic ethnicity has changed over time and then provide a conceptual projection of future trends.Cross-sectional, retrospective, analysis based on 11 years of publicly available data paired with recent US census population estimates.A total of 86,303 (2007-2008) to 103,539 (2017-2018) resident physicians in the 20 largest US Accreditation Council for Graduate Medical Education resident specialties.Changes in proportion of physician trainees of Black race and Hispanic ethnicity per academic year. Projected number of years it will then take, for specialties with positive changes, to reach proportions of Black race and Hispanic ethnicity comparable to that of the US population.Among the 20 largest specialty training programs, Radiology was the only specialty with a statistically significant increase in the proportion of Black trainees, but it could take Radiology 77 years to reach levels of Black representation comparable to that of the US population. Obstetrics/Gynecology, Emergency Medicine, Internal Medicine/Pediatrics, and Orthopedic Surgery demonstrated a statistically significant increase in the proportion of Hispanic trainees, but it could take these specialties 35, 54, 61, and 93 years respectively to achieve Hispanic representation comparable to that of the US population.Among US residents in the 20 largest specialties, no specialty represented either the Black or Hispanic populations in proportions comparable to the overall US population. Only a small number of specialties demonstrated statistically significant increases. This conceptual projection suggests that current efforts to promote diversity are insufficient.
View details for DOI 10.1007/s11606-021-06650-7
View details for PubMedID 33629264
Factors Associated with the Discordance between Perception of Being HIV Infected and HIV Sexual Risk Taking among Social Media-Using Black, Hispanic, and White Young Men Who Have Sex with Men.
Journal of the International Association of Providers of AIDS Care
; 19: 2325958220919260
Among HIV-uninfected, social media-using black, Hispanic, and white young men who have sex with men (YMSM) who had condomless anal sex but had not been HIV tested within the past year, we aimed to determine the extent of discordance between perception of having an undiagnosed HIV infection and HIV risk-taking behaviors. Despite reporting condomless anal sex without HIV testing, 64% of 358 YMSM participants perceived having an undiagnosed HIV infection as "unlikely" and 12% as "impossible." Having a primary care provider and being Hispanic were associated with greater discordance. Interventions to decrease the discordance between perceived and actual HIV risk are needed for this higher HIV risk population.
View details for DOI 10.1177/2325958220919260
View details for PubMedID 32314651
View details for PubMedCentralID PMC7175048
Supply and Demand of Emergency Medicine Board-certified Emergency Physicians by U.S. State, 2017.
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine
Our objective was to estimate the emergency medicine board-certified emergency physician (EMBC EP) workforce supply and demand by U.S. state.To estimate state demand, we applied the methodology from our 2005 analysis to calculate full-time equivalent (FTE) EMBC EP demand for each emergency department (ED). The 2017 National Emergency Department Inventory-USA provided visit volumes for all EDs, while the American Board of Medical Specialties supplied the 2017 number of EMBC EPs per state. Assuming at least one EMBC EP should be present 24/7 in each ED (requiring 5.35 FTEs minimum), we calculated the total FTEs required by dividing each ED's visit volume by the estimated average visits seen by an EMBC EP (3,548 visits per year), and then summed FTEs by state. The U.S. Census Bureau provided state demographic characteristics. We used multivariable linear regression to examine the association between state demographics and the density of EMBC EPs per state, and compared 2017 results to our prior 2005 analysis.There were 40,716 total EMBC EPs in 2017, fulfilling 77% of the estimated national demand. This was a substantial increase from 23,035 total EMBC EPs fulfilling 58% of demand in 2005. The 2017 supply ranged from 24% of demand in North Dakota to 142% in Hawaii. A lower density of EMBC EPs was associated with states in the Midwest and South (p<0.001) and with a more rural population (p=0.02). The absolute shortage of EMBC EPs worsened or remained the same in one-fourth of states.While the total number of EMBC EPs nearly doubled between 2005 and 2017, a shortage of full-time coverage persists. The supply and demand vary greatly by state. Worsening absolute shortages in several states show that the distribution of EMBC EPs is not meeting demand across the U.S, particularly in rural areas.
View details for DOI 10.1111/acem.14157
View details for PubMedID 33095959
Evaluation of two commercial and two non-commercial immunoassays for the detection of prior infection to SARS-CoV-2.
medRxiv : the preprint server for health sciences
Background Seroepidemiology is an important tool to characterize the epidemiology and immunobiology of SARS-CoV-2 but many immunoassays have not been externally validated raising questions about reliability of study findings. To ensure meaningful data, particularly in a low seroprevalence population, assays need to be rigorously characterized with high specificity. Methods We evaluated two commercial (Roche Diagnostics and Epitope Diagnostics IgM/IgG) and two non-commercial (Simoa and Ragon/MGH IgG) immunoassays against 68 confirmed positive and 232 pre-pandemic negative controls. Sensitivity was stratified by time from symptom onset. The Simoa multiplex assay applied three pre-defined algorithm models to determine sample result. Results The Roche and Ragon/MGH IgG assays each registered 1/232 false positive, the primary Simoa model registered 2/232 false positives, and the Epitope registered 2/230 and 3/230 false positives for the IgG and IgM assays respectively. Sensitivity >21 days post symptom-onset was 100% for all assays except Epitope IgM, but lower and/or with greater variability between assays for samples collected 9-14 days (67-100%) and 15-21 days (69-100%) post-symptom onset. The Simoa and Epitope IgG assays demonstrated excellent sensitivity earlier in the disease course. The Roche and Ragon/MGH IgG assays were less sensitive during early disease, particularly among immunosuppressed individuals. Conclusions The Epitope IgG demonstrated good sensitivity and specificity. The Roche and Ragon/MGH IgG assays registered rare false positives with lower early sensitivity. The Simoa assay primary model had excellent sensitivity and few false positives.
View details for DOI 10.1101/2020.06.24.20139006
View details for PubMedID 32607518
View details for PubMedCentralID PMC7325183
National Study of the Emergency Physician Workforce, 2020.
Annals of emergency medicine
We describe the current US emergency physician workforce.We analyzed the 2020 American Medical Association Physician Masterfile data set. All physicians who designated emergency medicine as their primary or secondary specialty were included; nonactive physicians, residents, primarily research or teaching faculty, or those primarily involved in administration or nonclinical work were excluded. We calculated emergency physician population density, using 2018 Census Bureau estimates of the US population; urban-rural assignments were based on Urban Influence Codes. We compared 2020 results with our previous analysis of the 2008 emergency physician workforce. Again, we were unable to account for American Osteopathic Board of Emergency Medicine certification.There were 48,835 clinically active emergency physicians in 2020. The median age was 50 years (interquartile range [IQR] 41 to 62 years) and 28% were women. Overall density of emergency physicians per 100,000 population was 14.9. Most emergency physicians were in urban areas (92%), whereas 2,730 (6%) were in large rural areas and 1,197 (2%) in small rural areas. Urban emergency physicians were younger (median age 50 years; IQR 41 to 61 years) than those in large rural areas (median age 58 years; IQR 47 to 67 years) or small rural areas (median age 62 years; IQR 51 to 68 years), and more likely to be women (29%, 20%, and 19%, respectively). Most emergency physicians in small rural areas (71%) completed their medical training more than 20 years ago. Compared with 2008, the total number of clinically active emergency physicians has increased by 9,774, but, per 100,000 US population in 2020, emergency physician density decreased in both large rural (-0.4) and small rural (-3.7) areas.Urban emergency physicians in 2020 remain substantially younger than rural emergency physicians, with many rural ones near the US retirement age. We did not observe a continued increase in the percentage of female physicians among emergency physicians. Given the ongoing demand for physicians in all US emergency departments, this analysis provides essential information for understanding the current emergency physician workforce and the challenges ahead.
View details for DOI 10.1016/j.annemergmed.2020.06.039
View details for PubMedID 32747085
Two decades of little change: An analysis of U.S. medical school basic science faculty by sex, race/ethnicity, and academic rank.
2020; 15 (7): e0235190
To examine changes in U.S. medical school basic science faculty over the last 20 years (1998-2018), we undertook an observational study utilizing data from the American Association of Medical Colleges Faculty Roster. Rank (Instructor, Assistant Professor, Associate Professor, and Professor), sex (Female), and race/ethnicity (Asian, Black or African American, Hispanic, Latino, Spanish Origin, or Multiple Race-Hispanic, and White) were analyzed; this reflected a population of 14,047 (1998) to 18,601 (2018) faculty. Summary percent of faculty in various gender, race/ethnicity origin categories were analyzed across years of the study using regression models. We found that females (24.47% to 35.32%) were underrepresented at all timepoints and a minority of faculty identified as Black or African American (1.57% to 1.99%), Hispanic, Latino, Spanish Origin, or Multiple Race-Hispanic (3.03% to 4.44%), or Asian (10.90% to 20.41%). The largest population at all time points was White Male Professors (30.53% to 20.85%), followed by White Male Associate Professors (15.67% to 9.34%), and White Male Assistant Professors (13.22% to 9.75%). Small statistically significant increases were observed among female faculty and faculty at multiple ranks who identified as Black or African American or Hispanic, Latino, Spanish Origin, or Multiple Race-Hispanic. We then completed secondary analyses looking at the interaction of race/ethnicity and Gender. We found: (1) a significant increase (p<0.0001) in both genders who identify as Asian although males had a higher rate of increase (6 point difference, p<0.0001); (2) a significant increase for Black or African American females (P<0.01) not found among males; (3) significant increases (p<0.0001) among both genders of faculty who identify as Hispanic, Latino, Spanish Origin, or Multiple Race-Hispanic although females had an approximately 1% higher rate of increase; and (4) among faculty who identify as White, males had a significant decrease (p<0.0001) while females demonstrated an increase (p<0.0001).
View details for DOI 10.1371/journal.pone.0235190
View details for PubMedID 32735593
View details for PubMedCentralID PMC7394429
- The Gender Gap in Surgical Residencies. JAMA surgery 2020
COVID-19: A Resident's Perspective
AEM Education and Training
2020; 4 (3)
View details for DOI 10.1002/aet2.10457
Gender Differences in Faculty Rank Among Academic Emergency Physicians in the United States.
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine
2019; 26 (3): 281–85
The purpose of this study was to complete a comprehensive analysis of gender differences in faculty rank among U.S. emergency physicians that reflected all academic emergency physicians.We assembled a comprehensive list of academic emergency medicine (EM) physicians with U.S. medical school faculty appointments from Doximity.com linked to detailed information on physician gender, age, years since residency completion, scientific authorship, National Institutes of Health (NIH) research funding, and participation in clinical trials. To estimate gender differences in faculty rank, multivariable logistic regression models were used that adjusted for these factors.Our study included 3,600 academic physicians (28%, or 1,016, female). Female emergency physicians were younger than their male colleagues (mean [±SD] age was 43.8 [±8.7] years for females and 47.4 [±9.9] years for males [p < 0.001]), had fewer years since residency completion (12.4 years vs. 15.6 years, p < 0.001), had fewer total and first/last author publications (4.7 vs. 8.6 total publications, p < 0.001; 4.3 vs. 7.1 first or last author publications, p < 0.001), and were less likely to be principal investigators on NIH grants (1.2% vs. 2.9%, p = 0.002) or clinical trials (1.8% vs. 4.4%, p < 0.001). In unadjusted analysis, male physicians were more likely than female physicians to hold the rank of associate or full professor versus assistant professor (13.7 percentage point difference, p < 0.001), a relationship that persisted after multivariable adjustment (5.5 percentage point difference, p = 0.001).Female academic EM physicians are less likely to hold the rank of associate or full professor compared to male physicians even after detailed adjustment for other factors that may influence faculty rank.
View details for DOI 10.1111/acem.13685
View details for PubMedID 30636377
- Changes in Sex, Race, and Ethnic Origin of Emergency Medicine Resident Physicians From 2007 to 2017. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine 2019; 26 (3): 331–34
- Annals Graphic Medicine - #ThisIsOurLane. Annals of internal medicine 2019; 170 (4): W78–W79
- In Reply. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine 2019; 26 (11): 1303
- Association of the 2003 and 2011 ACGME Resident Duty Hour Reforms With Internal Medicine Initial Certification Examination Performance. Journal of graduate medical education 2017; 9 (6): 789–90
A National Cross-Sectional Study of Surgery Residents Who Underreport Duty Hours.
Journal of surgical education
2017; 74 (6): 928–33
Previous work demonstrates that many surgery residents underreport duty hours. The purpose of this study was to identify characteristics of these residents and better understand why they exceed duty hours.During the winter of 2015 we conducted an anonymous cross-sectional survey of Accreditation Council for Graduate Medical Education accredited general surgery programs.A total of 101 general surgery residency programs across the United States.A total of 1003 general surgery residents across the United States. Respondents' mean age was 29.9 ± 3.0 years; 53% were male.Study response rate was 31.9%. Residents age <30 were more likely to exceed duty hours to complete charting/documentation (68% vs. 54%, p < 0.001). Females more often cited guilt about leaving the hospital (32% vs. 24%, p = 0.014) as to why they exceed duty hours. Programs with >40 residents had the highest rates of underreporting (82% vs. 67% in other groups p < 0.001) and residents who worked >90 hours on an average week more frequently cited external pressure (p = 0.0001), guilt (p = 0.006), and feeling it was expected of them (p < 0.0001) as reasons why they underreport compared to those who worked fewer hours.Underreporting and duty-hour violations are a complex issue influenced by many variables including age, sex, and internal and external pressures.
View details for DOI 10.1016/j.jsurg.2017.05.008
View details for PubMedID 28529194
Adult male with diffuse neck masses
Visual Journal of Emergency Medicine
View details for DOI 10.1016/j.visj.2017.04.019
Massive hemoptysis in Loeys-Dietz syndrome.
American journal of medical genetics. Part A
2016; 170 (3): 725–27
We describe four unrelated individuals with Loeys-Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective-tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature.
View details for DOI 10.1002/ajmg.a.37487
View details for PubMedID 26614122
A 15-Year-Old Male with Enlarging “Breast Lump”
Visual Journal of Emergency Medicine
View details for DOI 10.1016/j.visj.2016.01.009
- White (Coat) Lies: Bending the Truth to Stay Faithful to Patients. The American journal of bioethics : AJOB 2016; 16 (9): 15–17
- Surgical Resident Duty Hours. The New England journal of medicine 2016; 374 (24): 2399–2401
Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 1 Interacts with a Member of the Interferon-Stimulated Gene 15 Pathway.
Journal of virology
2015; 89 (22): 11572–83
Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus known to establish lifelong latency in the human host. We and others have previously shown that three KSHV homologs of cellular interferon regulatory factors (IRFs), known as viral IRFs (vIRFs), participate in evasion of the host interferon (IFN) response. We report that vIRF1 interacts with the cellular interferon-stimulated gene 15 (ISG15) E3 ligase, HERC5, in the context of Toll-like receptor 3 (TLR3) activation and IFN induction. The ISG15 protein is covalently conjugated to target proteins upon activation of the interferon response. Interaction between vIRF1 and HERC5 was confirmed by immunoprecipitation, and the region between amino acids 224 and 349 of vIRF1 was required for interaction with HERC5. We further report that expression of vIRF1 in the context of TLR3 activation results in decreased ISG15 conjugation of proteins. Specifically, TLR3-induced ISG15 conjugation and protein levels of cellular IRF3, a known ISG15 target, were decreased in the presence of vIRF1 compared to the control. vIRF1 itself was also identified as a target of ISG15 conjugation. KSHV-infected cells exhibited increased ISG15 conjugation upon reactivation from latency in coordination with increased IFN. Furthermore, knockdown of ISG15 in latently infected cells resulted in a higher level of KSHV reactivation and an increase in infectious virus. These data suggest that the KSHV vIRF1 protein affects ISG15 conjugation and interferon responses and may contribute to effective KSHV replication.The KSHV vIRF1 protein can inhibit interferon activation in response to viral infection. We identified a cellular protein named HERC5, which is the major ligase for ISG15, as a vIRF1 binding partner. vIRF1 association with HERC5 altered ISG15 modification of cellular proteins, and knockdown of ISG15 augmented reactivation of KSHV from latency.
View details for DOI 10.1128/JVI.01482-15
View details for PubMedID 26355087
View details for PubMedCentralID PMC4645652
The viral interferon regulatory factors of kaposi's sarcoma-associated herpesvirus differ in their inhibition of interferon activation mediated by toll-like receptor 3.
Journal of virology
2013; 87 (2): 798–806
Kaposi's sarcoma-associated herpesvirus (KSHV) infection is correlated with three human malignancies and can establish lifelong latent infection in multiple cell types within its human host. In order to establish and maintain infection, KSHV utilizes multiple mechanisms to evade the host immune response. One such mechanism is the expression of a family of genes with homology to cellular interferon (IFN) regulatory factors (IRFs), known as viral IRFs (vIRFs). We demonstrate here that KSHV vIRF1, -2, and -3 have a differential ability to block type I interferon signaling mediated by Toll-like receptor 3 (TLR3), a receptor we have previously shown to be activated upon KSHV infection. vIRF1, -2, and -3 inhibited TLR3-driven activation of IFN transcription reporters. However, only vIRF1 and vIRF2 inhibited increases in both IFN-β message and protein levels following TLR3 activation. The expression of vIRF1 and vIRF2 also allowed for increased replication of a virus known to activate TLR3 signaling. Furthermore, vIRF1 and vIRF2 may block TLR3-mediated signaling via different mechanisms. Altogether, this report indicates that vIRFs are able to block IFN mediated by TLRs but that each vIRF has a unique function and mechanism for blocking antiviral IFN responses.
View details for DOI 10.1128/JVI.01851-12
View details for PubMedID 23115281
View details for PubMedCentralID PMC3554052
KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.
2011; 43 (6): 601–6
KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.
View details for DOI 10.1038/ng.826
View details for PubMedID 21552264
View details for PubMedCentralID PMC3674836
A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.
2011; 43 (8): 776–84
Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.
View details for DOI 10.1038/ng.891
View details for PubMedID 21725307
View details for PubMedCentralID PMC3145011