Liise-anne Pirofski

Albert Einstein College of Medicine, New York City, New York, United States

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Publications (93)559.02 Total impact

  • Arturo Casadevall, Liise-anne Pirofski
    Nature 12/2014; 516(7530):165-6. · 38.60 Impact Factor
  • Arturo Casadevall, Liise-Anne Pirofski
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    ABSTRACT: Since proof of the germ theory of disease in the late 19(th) century a major focus of the fields of microbiology and infectious diseases has been to seek differences between pathogenic and non-pathogenic microbes and the role that the host plays in microbial pathogenesis. Remarkably, despite the increasing recognition that host immunity plays a role in microbial pathogenesis, there has been little discussion about what constitutes a host. Historically, hosts have been viewed in the context of their fitness or immunological status, and characterized by adjectives such as immune, immunocompetent, immunosuppressed, immunocompromised, or immunologically impaired. However, in recent years it has become apparent that the microbiota has profound effects on host homeostasis and susceptibility to microbial diseases in addition to its effects on host immunity. This raises the question of how to incorporate the microbiota into defining a host. This definitional problem is further complicated because neither host nor microbial properties are adequate to predict the outcome of host-microbe interaction because this outcome exhibits emergent properties. In this essay we revisit the 'damage-response framework' (DRF) of microbial pathogenesis and demonstrate how it can incorporate the rapidly accumulating information being generated by the microbiome revolution. We use the tenets of the DRF to put forth the following definition of a host: a host is an entity that houses an associated microbiome/microbiota and interacts with microbes such that the outcome results in damage, benefit, or indifference thus resulting in the states of symbiosis, colonization, commensalism, latency and disease.
    Infection and immunity. 11/2014;
  • Soma Rohatgi, L Pirofski
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    ABSTRACT: Accepted
    Future Microbiology 10/2014; · 4.02 Impact Factor
  • The Journal of Infectious Diseases 06/2014; · 5.85 Impact Factor
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    ABSTRACT: Extracellular vesicles are produced by many pathogenic microorganisms and have varied functions that include secretion and release of microbial factors, which contribute to virulence. Very little is known about vesicle production by Gram-positive bacteria, as well as their biogenesis and release mechanisms. In this work, we demonstrate the active production of vesicles by Streptococcus pneumoniae from the plasma membrane, rather than being a product from cell lysis. We biochemically characterized them by proteomics and fatty acid analysis, showing that these vesicles and the plasma membrane resemble in essential aspects, but have some differences: vesicles are more enriched in lipoproteins and short-chain fatty acids. We also demonstrate that these vesicles act as carriers of surface proteins and virulence factors. They are also highly immunoreactive against human sera and induce immune responses that protect against infection. Overall, this work provides insights into the biology of this important Gram-positive human pathogen and the role of extracellular vesicles in clinical applications. Pneumococcus is one of the leading causes of bacterial pneumonia worldwide in children and the elderly, being responsible for high morbidity and mortality rates in developing countries. The augment of pneumococcal disease in developed countries has raised major public health concern, since the difficulties to treat these infections due to increasing antibiotic resistance. Vaccination is still the best way to combat pneumococcal infections. One of the mechanisms that bacterial pathogens use to combat the defense responses of invaded hosts is the production and release of extracellular vesicles derived from the outer surface. Little is known about this phenomenon in Gram-positives. We show that pneumococcus produces membrane-derived vesicles particularly enriched in lipoproteins. We also show the utility of pneumococcal vesicles as a new type of vaccine, as they induce protection in immunized mice against infection with a virulent strain. This work will contribute to understand the role of these structures in important biological processes such as host-pathogen interactions and prevention of human disease.
    Journal of proteomics 04/2014; · 5.07 Impact Factor
  • Joshua Vernatter, Liise-Anne Pirofski
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    ABSTRACT: PURPOSE OF REVIEW: Infection with Streptococcus pneumoniae (pneumococcus) results in colonization, which can lead to local or invasive disease, of which pneumonia is the most common manifestation. Despite the availability of pneumococcal vaccines, pneumococcal pneumonia is the leading cause of community and inhospital pneumonia in the United States and globally. This article discusses new insights into the pathogenesis of pneumococcal disease. RECENT FINDINGS: The host-microbe interactions that determine whether pneumococcal colonization will result in clearance or invasive disease are highly complex. This article focuses on new information in three areas that bear on the pathogenesis of pneumococcal disease: factors that govern colonization, the prelude to invasive disease, including effects on colonization and invasion of capsular serotype, pneumolysin, surface proteins that regulate complement deposition, biofilm formation and agglutination; the effect of coinfection with other bacteria and viruses on pneumococcal growth and virulence, including the synergistic effect of influenza virus; and the contribution of the host inflammatory response to the pathogenesis of pneumococcal pneumonia, including the effects of pattern recognition molecules, cells that enhance and modulate inflammation, and therapies that modulate inflammation, such as statins. SUMMARY: Recent research on pneumococcal pathogenesis reveals new mechanisms by which microbial factors govern the ability of pneumococcus to progress from the state of colonization to disease and host inflammatory responses contribute to the development of pneumonia. These mechanisms suggest that therapies which modulate the inflammatory response could hold promise for ameliorating damage stemming from the host inflammatory response in pneumococcal disease.
    Current Opinion in Infectious Diseases 04/2013; · 5.03 Impact Factor
  • Arturo Casadevall, Liise-Anne Pirofski
    Future Microbiology 02/2013; 8:135-7. · 4.02 Impact Factor
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    ABSTRACT: ABSTRACT Bruton's tyrosine kinase (Btk) is a signaling molecule that plays important roles in B-1 B cell development and innate myeloid cell functions and has recently been identified as a target for therapy of B cell lymphomas. We examined the contribution of B-1 B cells to resistance to Cryptococcus neoformans infection by utilizing X-linked immunodeficient (XID) mice (CBA-CaHN-XID), which possess a mutation in Btk. XID mice had significantly higher brain fungal burdens than the controls 6 weeks after infection with C. neoformans strain 52D (CN52D); however, consistent with the propensity for greater virulence of C. neoformans strain H99 (CNH99), CNH99-infected XID mice had higher lung and brain fungal burdens than the controls 3 weeks after infection. Further studies in a chronic CN52D model revealed markedly lower levels of total and C. neoformans-specific serum IgM in XID mice than in the control mice 1 and 6 weeks after infection. Alveolar macrophage phagocytosis was markedly impaired in CN52D-infected XID mice compared to the controls, with XID mice exhibiting a disorganized lung inflammatory pattern in which Gomori silver staining revealed significantly more enlarged, extracellular C. neoformans cells than the controls. Adoptive transfer of B-1 B cells to XID mice restored peritoneal B-1 B cells but did not restore IgM levels to those of the controls and had no effect on the brain fungal burden at 6 weeks. Taken together, our data support the hypothesis that IgM promotes fungal containment in the lungs by enhancing C. neoformans phagocytosis and restricting C. neoformans enlargement. However, peritoneal B-1 B cells are insufficient to reconstitute a protective effect in the lungs. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that causes an estimated 600,000 deaths per year. Most infections occur in individuals who are immunocompromised, with the majority of cases occurring in those with HIV/AIDS, but healthy individuals also develop disease. Immunoglobulin M (IgM) has been linked to resistance to disease in humans and mice. In this article, we found that X-linked immunodeficient (XID) mice, which have markedly reduced levels of IgM, were unable to contain Cryptococcus in the lungs. This was associated with reduced yeast uptake by macrophages, an aberrant tissue inflammatory response, an enlargement of the yeast cells in the lungs, and fungal dissemination to the brain. Since XID mice have a mutation in the Bruton's tyrosine kinase (Btk) gene, our data suggest that treatments aimed at blocking the function of Btk could pose a higher risk for cryptococcosis.
    mBio 01/2013; 4(4). · 6.88 Impact Factor
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    ABSTRACT: ABSTRACT Cryptococcus neoformans is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4(+) T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1; P = 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4(+) T cell decline, and nadir CD4(+) T cell count (OR, 21; P = 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote C. neoformans pathogenesis via increased binding of C. neoformans immune complexes, resulting in increased phagocyte cargo and/or immune activation. IMPORTANCE HIV-associated CD4(+) T cell deficiency is a sine qua non for HIV-associated cryptococcal disease (CD), but not all patients with CD4(+) T cell deficiency develop CD despite serological evidence of previous infection. At present, there are no biomarkers that predict HIV-associated CD risk. The goal of our study was to understand whether Fc gamma receptor (FCGR) polymorphisms that have been shown to portend CD risk in HIV-uninfected people are associated with CD risk in HIV-infected people. Such biomarkers could identify those who would benefit most from targeted prophylaxis and/or earlier treatment, particularly in sub-Saharan Africa, where there are nearly a million cases of HIV-associated CD annually. A biomarker of risk could also identify potential candidates for immunization, should there be a vaccine for Cryptococcus neoformans.
    mBio 01/2013; 4(5). · 6.88 Impact Factor
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    Soma Rohatgi, Liise-Anne Pirofski
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    ABSTRACT: The role of B cells in host defense against fungi has been difficult to establish. We quantified and determined the molecular derivation of B-1a, B-1b, and B-2 B cell populations in C57BL/6 mice after pulmonary infection with Cryptococcus neoformans. Total B-1 and B-2 cell numbers increased in lungs and peritoneal cavity as early as day 1 postinfection, but lacked signs of clonal expansion. Labeled capsular (24067) and acapsular (Cap67) C. neoformans strains were used to identify C. neoformans-binding B cell subsets by flow cytometry. Peritoneal cavity B-1a B cells exhibited the most acapsular and capsular C. neoformans binding in C. neoformans-infected mice, and C. neoformans-selected B-1 B cells secreted laminarin- and C. neoformans-binding IgM. Single-cell PCR-based sequence analysis of B-1a, B-1b, and B-2 cell IgH V region H chain (V(H)) genes revealed increased usage of V(H)11 and V(H)12, respectively, in acapsular and capsular C. neoformans-selected B-1a cells. Germline V(H) segments were used, with capsular C. neoformans-selected cells having less junctional diversity than acapsular C. neoformans-selected cells. Further studies in B-1 B cell-depleted mice showed that these mice had higher brain and lung fungal burdens and less alveolar macrophage phagocytosis of C. neoformans than did control and B-1a B cell-reconstituted mice. Taken together, these results establish a mechanistic role for B-1 B cells in the innate B cell response to pulmonary infection with C. neoformans and reveal that IgM-producing B-1a cells, which express germline V(H) genes, bind C. neoformans and contribute to early fungal clearance. Thus, B-1a B cells provide a first line of defense during pulmonary C. neoformans infection in mice.
    The Journal of Immunology 11/2012; · 5.52 Impact Factor
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    ABSTRACT: Background: We previously presented data suggesting that in HIV+ with CD4 >200, delaying PV until ≥6 months (m) of ART did not improved IgG responses to 5 pneumococcal capsular polysaccharides (CPS). Responses to PV are driven by IgM memory B lymphocytes; this B cell population is markedly impaired with HIV. We hypothesized that ≥6 of ART and controlled viremia would enhance specific anti-CPS IgM responses and opsonophagocytic activity (OPA). Methods: HIV+, CD4 >200, not on ART, and no PV in 3 years were eligible. 109 patients were randomized to Immediate (Imm) (PV prior to ART and placebo at 12m) or Delayed (Del) (baseline placebo and PV at 12m) -groups. Outcomes were pre to 1-m post-PV IgM, IgG and OPA increases for CPS 6B and 23F, and % of responders for each. Response was defined as >4-fold increase in OPA titer, and >2-fold increase in IgG and IgM level with post-PV ≥1 μg/ml. Results: For 56 subjects for whom IgG, IgM and OPA for CPS 6B and 23F were completed. Characteristics for Imm vs. Del groups at PV were: Age, 41 vs. 44 (P =0.3), median CD4 and log viral load (VL), 296 vs. 473 and 5 vs. 2, respectively (P <0.01 for both comparisons); 59% of subjects in Del group had VL <50 RNA copies/mL (vs. none in Imm). Geometric mean (GM) IgM and IgG levels (μg/ml) and OPA titers (+SD): CPS Immediate (N=23) Delayed (N=33) IgM IgG OPA IgM IgG OPA Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post 6B 1.6 ±1.4 1.8 ±1.5 3.8 ±2.5 6.2 ±8.1 4.4 ±108 23.0* ±178 1.9 ±1.0 2.2* ±1.6 4.7 ±3.3 5.5* ±4.2 4.7 ±97 14.7 ±110 Responders 0% 26% 57% 12% 12% 36% 23F 0.6 ±0.9 0.6 +0.7 1.3 ±1.2 1.9* +1.7 2.9 ±7 4.7 ±29 0.8 ±0.9 0.8 ±0.6 1.7 ±0.9 2.2* ±2.8 2.4 ±2.5 3.4 ±12 Responders 9% 13% 26% 6% 18% 15% *P <0.05 compared to pre-PV. There were no significant differences in the GM IgM or IgG levels, or OPA titers between groups. Del group had significant pre- to post-PV increases for IgM and IgG for 6B, and for IgG for 23F, but not for OPA for either; while Imm group had significant IgG and OPA increases for 23F and 6B, respectively; % of responders to IgM, IgG or OPA were similar (P >0.05). Conclusion: Overall, post-PV IgM, IgG or OPA responses to the 2 CPS tested were similar between the 2 groups. Results suggest that in HIV+ with CD4 >200, delaying PV until ≥6 m of ART does not lead to improved quantitative or qualitative anti-CPS antibody responses.
    IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012
  • Conference Paper: Fungal Infection Update
    Liise-anne Pirofski
    IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012
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    ABSTRACT: B7x (B7-H4 or B7S1), a member of the B7 family, inhibits in vitro T cell proliferation and cytokine production by binding to an unidentified receptor on activated T cells, but its in vivo function remains largely unclear. We show that B7x protein was expressed in epithelial cells of the lung, but not in lymphoid tissues. To investigate the role of B7x in the lung, we determined the susceptibility of B7x-deficient (B7x(-/-)) mice to a lethal pulmonary infection with Streptococcus pneumoniae. B7x(-/-), but not B7-H3-deficient, mice were significantly more resistant to S. pneumoniae pulmonary infection than their wild-type (Wt) counterparts. B7x(-/-) mice had significantly lower bacterial burdens and levels of inflammatory cytokines in lungs as early as 12 h postinfection. They also had milder immunopathology that was localized in alveolar spaces, whereas Wt mice had severe inflammation that was perivascular. Control of infection in B7x(-/-) mice was associated with a marked increase in activated CD4 and CD8 T cells and fewer neutrophils in lungs, whereas the susceptible Wt mice had the opposite cellular profile. In B7x(-/-)Rag1(-/-) mice that lack T cells, reduction in bacterial burden was no longer observed. Control of S. pneumoniae and the increased survival observed was specific to the lung, because systemically infected B7x(-/-) mice were not resistant to infection. These data indicate that lung-expressed B7x negatively regulates T cells, and that in its absence, in B7x(-/-) mice, an enhanced T cell response contributed to reduced lethality in a pulmonary infection model with S. pneumoniae.
    The Journal of Immunology 08/2012; 189(6):3054-63. · 5.52 Impact Factor
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    Arturo Casadevall, Liise-Anne Pirofski
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    ABSTRACT: Only two decades ago antibodies to fungi were thought to have little or no role in protection against fungal diseases. However, subsequent research has provided convincing evidence that certain antibodies can modify the course of fungal infection to the benefit or detriment of the host. Hybridoma technology was the breakthrough that enabled the characterization of antibodies to fungi, illuminating some of the requirements for antibody efficacy. As discussed in this review, fungal-specific antibodies mediate protection through direct actions on fungal cells and through classical mechanisms such as phagocytosis and complement activation. Although mechanisms of antibody-mediated protection are often species-specific, numerous fungal antigens can be targeted to generate vaccines and therapeutic immunoglobulins. Furthermore, the study of antibody function against medically important fungi has provided fresh immunological insights into the complexity of humoral immunity that are likely to apply to other pathogens.
    Cell host & microbe 05/2012; 11(5):447-56. · 13.02 Impact Factor
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    Wendy A Szymczak, Rani S Sellers, Liise-anne Pirofski
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    ABSTRACT: The cytokines IL-23 and IL-17 have been implicated in resistance to cryptococcal disease, but it is not clear whether IL-23-mediated production of IL-17 promotes fungal containment following pulmonary challenge with Cryptococcus neoformans. We used mice lacking IL-23 (IL-23p19(-/-)) or IL-17RA (IL-17RA(-/-)), and wild type (WT) C57BL/6 mice to examine the IL-23/IL-17 axis after intranasal infection with the C. neoformans strain 52D. The absence of IL-23 or IL-17RA had no effect on pulmonary or brain fungal burden at 1 or 6 weeks after infection. However, survival of IL-23p19(-/-) mice was reduced compared to IL-17RA(-/-) mice. IL-I7 production by CD4 T cells and natural killer T (NKT) cells was impaired in IL-23p19(-/-) lungs, but was not completely abolished. Both IL-23p19(-/-) and IL-17RA(-/-) mice exhibited impaired neutrophil recruitment, increased serum levels of IgE and IgG2b, and increased deposition of YM1/YM2 crystals in the lung, but only IL-23p19(-/-) mice developed persistent lung eosinophilia. Although survival of IL-17RA(-/-) and WT mice was similar after 17 weeks of infection, only surviving IL-17RA(-/-) mice exhibited cryptococcal dissemination to the blood. These data demonstrate that IL-23 dampens the allergic response to cryptococcal infection through IL-17-independent suppression of eosinophil recruitment and IL-17-dependent regulation of antibody production and crystal deposition. Furthermore, IL-23, and to a lesser extent IL-17, contribute to disease resistance.
    American Journal Of Pathology 02/2012; 180(4):1547-59. · 4.60 Impact Factor
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    ABSTRACT: Bacterial pneumonia risk is disproportionately high among those infected with HIV. This risk is present across all CD4(+) T-cell levels (TCLs), suggesting that additional factors govern susceptibility. This study examines CD8(+) TCLs and risk for HIV-associated bacterial pneumonia and all-cause mortality. Demographic, clinical, and laboratory data were obtained for 885 HIV-infected women enrolled in the HIV Epidemiologic Research Study (HERS). Bacterial pneumonia cases were identified using clinical, microbiological, and radiographic criteria. CD8(+) TCLs were assessed at 6-month intervals. Statistical methods included Cox proportional hazards regression modeling and covariate-adjusted survival estimates. Relative to a referent CD8(+) TCL of 401-800 cells per cubic millimeter, risk for bacterial pneumonia was significantly higher when CD8(+) TCLs were <400 (hazard ratio 1.65, P = 0.017, 95% confidence interval 1.10 to 2.49), after adjusting for age, CD4(+) TCL, viral load, and antiretroviral use. There was also a significantly higher risk of death when CD8(+) TCLs were ≤400 cells per cubic millimeter (hazard ratio 1.45, P = 0.04, 95% confidence interval 1.02 to 2.06). Covariate-adjusted survival estimates revealed shorter time to pneumonia and death in this CD8(+) TCL category, and the overall associations of the categorized CD8(+) TCL with bacterial pneumonia and all-cause mortality were each statistically significant (P = 0.017 and P < 0.0001, respectively). CD8(+) TCL ≤400 cells per cubic millimeter was associated with increased risk for pneumonia and all-cause mortality in HIV-infected women in the HERS cohort, suggesting that CD8(+) TCL could serve as an adjunctive biomarker of pneumonia risk and mortality in HIV-infected individuals.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2012; 60(2):191-8. · 4.65 Impact Factor
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    Sarah Weber, Haijun Tian, Nico van Rooijen, Liise-Anne Pirofski
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    ABSTRACT: Antibodies to pneumococcal capsular polysaccharide (PPS) are required for PPS-based vaccine-mediated protection against Streptococcus pneumoniae. Previous work established that 1E2, a mouse IgG1 to PPS3 that does not induce serotype 3 (ST3) S. pneumoniae killing by phagocytes in vitro, protects mice from death after intranasal infection with ST3, but its efficacy was abrogated in FcγR (F common gamma receptor)-deficient mice. In this study, we determined whether 1E2 efficacy against pulmonary ST3 infection requires FcγRIII. 1E2 did not protect FcγRIII-deficient (FcγRIII(-/-)) mice. Studies of the mechanism of 1E2-mediated effects showed that it resulted in a marked reduction in lung inflammation in ST3-infected wild-type (Wt [C57BL/6]) mice that was abrogated in FcγRIII(-/-) mice. 1E2 had no effect on early bacterial clearance in the lungs of ST3-infected Wt, FcγRIIB(-/-), or FcγRIII(-/-) mice, but it reduced levels of bacteremia and serum macrophage inflammatory protein-2) (MIP-2), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in Wt and FcγRIIB(-/-) mice, strains in which it is protective. As previous work showed that neutrophils were dispensable for 1E2 efficacy, we investigated whether macrophages are required for 1E2 efficacy against intranasal infection with ST3 and found that its efficacy was abrogated in Wt mice depleted of macrophages intranasally. In vitro studies revealed that1E2 promoted ST3 internalization by naïve alveolar macrophages but did not induce early intracellular killing. Macrophages from 1E2-treated ST3-infected mice studied ex vivo exhibited more apoptosis than those from FcγRIII(-/-) mice. These findings suggest that 1E2 mediates protection against ST3 in mice by affecting the inflammatory response, perhaps in part via macrophage apoptosis, rather than by inducing early bacterial clearance.
    Infection and immunity 01/2012; 80(4):1314-22. · 4.21 Impact Factor
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    Liise-anne Pirofski, Arturo Casadevall
    BMC Biology 01/2012; 10:6. · 7.43 Impact Factor
  • Kieren A Marr, Kausik Datta, Liise-anne Pirofski, Robert Barnes
    Clinical Infectious Diseases 11/2011; 54(1):153-4. · 9.37 Impact Factor
  • Conference Paper: Fungal Infection Update
    Liise-anne Pirofski
    Infectious Diseases Society of America 2011 Annual Meeting; 10/2011

Publication Stats

2k Citations
559.02 Total Impact Points

Institutions

  • 1995–2014
    • Albert Einstein College of Medicine
      • • Department of Microbiology & Immunology
      • • Infectious Diseases
      • • Department of Medicine
      New York City, New York, United States
  • 2012
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2007
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States