Allen G Harmsen

Montana State University, Bozeman, Montana, United States

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Publications (60)317.45 Total impact

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    ABSTRACT: Superinfection in mice at day 7 post-influenza infection exacerbates bacterial pneumonia at least in part via downstream effects of increased IFN-γ signaling. Here we show that up to 3 days post-influenza infection, mice have reduced susceptibility to superinfection with methicillin-resistant Staphylococcus aureus (MRSA), but that superinfection during that time exacerbated influenza disease. This was due to IL-13 signaling that was advantageous for resolving MRSA infection via inhibition of IFN-γ, but was detrimental to the clearance of influenza virus. However, if superinfection did not occur until the near resolution of influenza infection (day 7), IL-13 signaling was inhibited, at least in part by upregulation of IL-13 decoy receptor (IL-13Rα2), which in turn caused increases in IFN-γ signaling and exacerbation of bacterial infection. Understanding these cytokine sequelae is critical to development of immunotherapies for influenza-MRSA coinfection since perturbations of these sequelae at the wrong time could increase susceptibility to MRSA and/or influenza.This article is protected by copyright. All rights reserved
    European Journal of Immunology 08/2014; · 4.97 Impact Factor
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    ABSTRACT: Abstract Background: Exposure of the lungs to an antigen or pathogen elicits the formation of lymphoid satellite islands termed inducible bronchus-associated lymphoid tissue (iBALT). However, little is known about how the presence of iBALT, induced by a stimulus unrelated to the subsequent challenge agent, influences systemic immunity in distal locations, whether it be independently, antagonistically, or synergistically. Here, we determined the kinetics of the influenza-specific responses in the iBALT, tracheobronchial lymph node (TBLN), and spleen of mice with and without pre-formed iBALT. Methods and Results: Mice with VLP-induced iBALT or no pre-formed iBALT were challenged with influenza. We found that, as we have previously described, those mice whose lungs contained pre-formed iBALT were protected from morbidity, and furthermore, that these mice had increased dendritic cell, and alveolar macrophage accumulation in both the iBALT and TBLNs. This translated to similarly accelerated kinetics and intensified influenza-specific CD4(+), but not CD8(+) T cell responses in the iBALT, TBLN, and spleen. This expansion was then followed by a more rapid T cell contraction in all lymphoid tissues in the mice with pre-formed iBALT. Conclusions: Thus, iBALT itself may not be responsible for the accelerated primary immune response we observe in mice with pre-formed iBALT, but may contribute to an overall accelerated local and systemic primary CD4(+), but not CD8(+) T cell response. Furthermore, less damaging immune responses observed in mice with pre-formed iBALT may be due to a quicker contraction of CD4(+) T cell responses in both local and systemic secondary lymphoid tissue.
    Lymphatic Research and Biology 12/2013; 11(4):196-202. · 2.33 Impact Factor
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    ABSTRACT: Recent evidence suggests that an individual's unique history and sequence of exposures to pathogens and antigens may dictate downstream immune responses to disparate antigens. We show that the intranasal delivery of non-replicative virus-like particles (VLPs), which bear structural but no antigenic similarities to respiratory pathogens, acts to prime the lungs of both C56BL/6 and BALB/c mice, facilitating heightened and accelerated primary immune responses to high-dose influenza challenge, thus providing a non-pathogenic model of innate imprinting. These responses correspond closely to those observed following natural infection with the opportunistic fungus, Pneumocystis murina, and are characterized by accelerated antigen processing by dendritic cells (DCs) and alveolar macrophages (AMs), an enhanced influx of cells to the local tracheobronchial lymph node (TBLN), and early upregulation of T-cell co-stimulatory/adhesion molecules. CD11c(+) cells which have been directly exposed to VLPs or Pneumocystis are necessary in facilitating enhanced clearance of influenza virus, and the repopulation of the lung by Ly-6C(+) precursors relies on CCR2 expression. Thus, immune imprinting 72 hours after VLP-, or 2 weeks after Pneumocystis-priming is CCR2-mediated and results from the enhanced antigen processing, maturation, and trafficking abilities of DCs and AMs, which cause accelerated influenza-specific primary immune responses and result in superior viral clearance. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 11/2013; · 4.97 Impact Factor
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    ABSTRACT: Here we present a biomimetic strategy for nanoparticle design for controlled immune response through encapsulation of conserved internal influenza proteins on the interior of virus like particles (VLPs) to direct CD8+ cytotoxic T cell protection. Programmed encapsulation and sequestration of the conserved nucleoprotein (NP) from influenza on the interior of the VLP derived from the bacteriophage P22 results in a vaccine that provides multi-strain protection against 100 times lethal doses of influenza in an NP specific CD8+ T cell-dependent manner. VLP assembly and encapsulation of the immunogenic NP cargo protein is the result of a genetically programmed self-assembly making this strategy amendable to the quick production of vaccines to rapidly emerging pathogens. Addition of adjuvants or targeting molecules were not required for eliciting the protective response.
    ACS Nano 03/2013; · 12.03 Impact Factor
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    ABSTRACT: The importance of the priming of the lung environment by past infections is being increasingly recognized. Exposure to any given antigen can either improve or worsen the outcome of subsequent lung infections, depending on the immunological history of the host. Thus, an ability to impart transient alterations in the lung environment in anticipation of future insult could provide an important novel therapy for emerging infectious diseases. In this study, we show that nasal administration of virus-like particles (VLPs) before, or immediately after, lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA) of mice i) ensures complete recovery from lung infection and near absolute clearance of bacteria within 12 hours of challenge, ii) reduces host response-induced lung tissue damage, iii) promotes recruitment and efficient bacterial clearance by neutrophils and CD11c(+) cells, and iv) protects macrophages from MRSA-induced necrosis. VLP-mediated protection against MRSA relied on innate immunity. Complete recovery occurred in VLP-dosed mice with severe combined immunodeficiency, but not in wild-type mice depleted of either Ly6G(+) or CD11c(+) cells. Early IL-13 production associated with VLP-induced CD11c(+) cells was essential for VLP-induced protection. These results indicate that VLP-induced alteration of the lung environment protects the host from lethal MRSA pneumonia by enhancing phagocyte recruitment and killing and by reducing inflammation-induced tissue damage via IL-13-dependent mechanisms.
    American Journal Of Pathology 05/2012; 181(1):196-210. · 4.60 Impact Factor
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    ABSTRACT: We show that a model antigen, ovalbumin (OVA), can be chemically conjugated to the exterior of a small heat shock protein (sHsp) cage that has structural similarities to virus-like particles (VLPs). OVA-sHsp conjugation efficiency was dependent upon the stoichiometry and the length of the small molecule linker utilized, and the attachment position on the sHsp cage. When conjugated OVA-sHsp was delivered intranasally to naïve mice, the resulting immune response to OVA was accelerated and intensified, and OVA-specific IgG1 responses were apparent within 5 days after a single immunizing dose, illustrating its utility for vaccine development. If animals were pretreated with a disparate VLP, P22 (a non-replicative bacteriophage capsid), before OVA-sHsp conjugate immunization, OVA-specific IgG1 responses were apparent already by 4 days after a single immunizing dose of conjugate in OVA-naïve mice. Additionally, the mice pretreated with P22 produced high titer mucosal IgA, and isotype-switched OVA-specific serum IgG. Similarly, sHsp pretreatment enhanced the accumulation of lung germinal center B cells, T follicular helper cells, and increased polymeric Ig receptor expression, priming the lungs for subsequent IgG and IgA responses to influenza virus challenge. Thus, sHsp nanoparticles elicited quick and intense antibody responses and these accelerated responses could similarly be induced to antigen chemically conjugated to the sHsp. Pretreatment of mice with P22 further accelerated the onset of the antibody response to OVA-sHsp, demonstrating the utility of conjugating antigens to VLPs for pre-, or possibly post-exposure prophylaxis of lung, all without the need for adjuvant.
    Vaccine 03/2012; 30(24):3653-65. · 3.77 Impact Factor
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    ABSTRACT: Coxiella burnetii, the causative agent of Q fever, is a zoonotic disease with potentially life-threatening complications in humans. Inhalation of low doses of Coxiella bacteria can result in infection of the host alveolar macrophage (AM). However, it is not known whether a subset of AMs within the heterogeneous population of macrophages in the infected lung is particularly susceptible to infection. We have found that lower doses of both phase I and phase II Nine Mile C. burnetii multiply and are less readily cleared from the lungs of mice compared to higher infectious doses. We have additionally identified AM resident within the lung prior to and shortly following infection, opposed to newly recruited monocytes entering the lung during infection, as being most susceptible to infection. These resident cells remain infected up to twelve days after the onset of infection, serving as a permissive niche for the maintenance of bacterial infection. A subset of infected resident AMs undergo a distinguishing phenotypic change during the progression of infection exhibiting an increase in surface integrin CD11b expression and continued expression of the surface integrin CD11c. The low rate of phase I and II Nine Mile C. burnetii growth in murine lungs may be a direct result of the limited size of the susceptible resident AM cell population.
    PLoS ONE 01/2012; 7(12):e51941. · 3.53 Impact Factor
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    ABSTRACT: It is widely held that exposure to pathogens such as fungi can be an agent of comorbidity, such as exacerbation of asthma or chronic obstructive pulmonary disease. Although many studies have examined allergic responses to fungi and their effects on pulmonary function, the possible pathologic implications of the early innate responses to fungal pathogens have not been explored. We examined early responses to the atypical fungus Pneumocystis in two common strains of mice in terms of overall immunological response and related pathology, such as cell damage and airway hyperresponsiveness (AHR). We found a strong strain-specific response in BALB/c mice that included recruitment of neutrophils, NK, NKT, and CD4 T cells. This response was accompanied by elevated indicators of lung damage (bronchoalveolar lavage fluid albumin and LDH) and profound AHR. This early response was absent in C57BL/6 mice, although both strains exhibited a later response associated with the clearance of Pneumocystis. We found that this AHR could not be attributed exclusively to the presence of recruited neutrophils, NKT, NK, or CD4 cells or to the actions of IFN-γ or IL-4. However, in the absence of STAT6 signaling, AHR and inflammatory cell recruitment were virtually absent. Gene expression analysis indicated that this early response included activation of several transcription factors that could be involved in pulmonary remodeling. These results show that exposure to a fungus such as Pneumocystis can elicit pulmonary responses that may contribute to morbidity, even without prior sensitization, in the context of certain genetic backgrounds.
    American Journal of Respiratory Cell and Molecular Biology 09/2011; 46(3):290-8. · 4.15 Impact Factor
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    ABSTRACT: Infection with the opportunistic fungal pathogen Pneumocystis is assumed to pass without persistent pathology in immunocompetent hosts. However, when immunocompetent BALB/c mice were inoculated with Pneumocystis, a vigorous Th2-like pulmonary inflammation ensued and peaked at 14 days postinfection. This coincided with a 10-fold increase in the number of antigen-presenting cells (APCs) in the lung, and these cells were capable of presenting antigen in vitro, as well as greater uptake of antigen in vivo. When mice were presented with exogenous antigen at the 14-day time point of the infection, they developed respiratory sensitization to that antigen, in the form of increased airway hyperresponsiveness upon a later challenge, whereas mice not infected but presented with antigen did not. Like other forms of collateral sensitization, this response was dependent on interleukin-4 receptor signaling. This ability to facilitate sensitization to exogenous antigen has been previously reported for other infectious disease agents; however, Pneumocystis appears to be uniquely capable in this respect, as a single intranasal dose without added adjuvant, when it was administered at the appropriate time, was sufficient to initiate sensitization. Pneumocystis infection probably occurs in most humans during the first few years of life, and in the vast majority of cases, it fails to cause any overt direct pathology. However, as we show here, Pneumocystis can be an agent of comorbidity at this time by facilitating respiratory sensitization that may relate to the later development or exacerbation of obstructive airway disease.
    Infection and immunity 02/2011; 79(5):1905-14. · 4.21 Impact Factor
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    ABSTRACT: Coxiella burnetii is an obligate intracellular gram-negative bacterium that causes acute Q fever and chronic infections in humans. A killed, whole cell vaccine is efficacious, but vaccination can result in severe local or systemic adverse reactions. Although T cell responses are considered pivotal for vaccine derived protective immunity, the epitope targets of CD4(+) T cell responses in C. burnetii vaccination have not been elucidated. Since mapping CD4(+) epitopes in a genome with over 2,000 ORFs is resource intensive, we focused on 7 antigens that were known to be targeted by antibody responses. 117 candidate peptides were selected from these antigens based on bioinformatics predictions of binding to the murine MHC class II molecule H-2 IA(b). We screened these peptides for recognition by IFN-γ producing CD4(+) T cell in phase I C. burnetii whole cell vaccine (PI-WCV) vaccinated C57BL/6 mice and identified 8 distinct epitopes from four different proteins. The identified epitope targets account for 8% of the total vaccination induced IFN-γ producing CD4(+) T cells. Given that less than 0.4% of the antigens contained in C. burnetii were screened, this suggests that prioritizing antigens targeted by antibody responses is an efficient strategy to identify at least a subset of CD4(+) targets in large pathogens. Finally, we examined the nature of linkage between CD4(+) T cell and antibody responses in PI-WCV vaccinated mice. We found a surprisingly non-uniform pattern in the help provided by epitope specific CD4(+) T cells for antibody production, which can be specific for the epitope source antigen as well as non-specific. This suggests that a complete map of CD4(+) response targets in PI-WCV vaccinated mice will likely include antigens against which no antibody responses are made.
    PLoS ONE 01/2011; 6(3):e17712. · 3.53 Impact Factor
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    ABSTRACT: Immune-reconstitution after highly active antiretroviral therapy (HAART) is often incomplete, and some HIV-infected individuals fail to regenerate type-I interferon (IFN)-producing pDCs. We recently demonstrated that during Pneumocystis (PC) infection in CD4 T cell-competent mice the absence of type-I IFN signaling results in chronic pulmonary inflammation and fibrosis despite clearance. Because the mechanisms involved are poorly understood, we further characterized the role of type-I IFN signaling in immune responses to PC. We show that type-I IFN signaling around day 7 postinfection is critical to the outcome of inflammation. Microarray analysis of pulmonary CD11c(+) cells revealed that at day 7 post infection, wild-type cells up-regulated type-I IFN-responsive genes as well as SOCS1, which is a critical negative-regulator of type-I IFN and IFN-gamma signaling. This was associated with an eosinophilic lung inflammation, PC clearance, and complete restitution. However, pulmonary CD11c(+) cells from IFNAR(-/-) mice demonstrated increased tumor necrosis factor (TNF)-alpha production and lacked SOCS1-induction at day 7. This was followed by a transient lymphocytic and IFN-gamma response before switching to a chronic eosinophilic inflammation of the lung. Early neutralization of TNF-alpha did not prevent chronic inflammation in IFNAR(-/-) mice, but treatment with an anti-IFN-gamma antibody did. We propose that during PC lung infection type-I IFNs induce SOCS1-associated regulatory mechanisms, which prevent excessive IFN-gamma-mediated responses that cause chronic lung damage. Therefore, partial immune-reconstitution in AIDS, attributable to reduced type-I IFN actions, might disrupt regulatory aspects of inflammation, causing unexplained chronic pulmonary complications as seen in some patients during HAART.
    American Journal Of Pathology 06/2010; 176(6):2806-18. · 4.60 Impact Factor
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    Quinton O King, Benfang Lei, Allen G Harmsen
    The Journal of Infectious Diseases 04/2010; 201(8):1273. · 5.85 Impact Factor
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    Amanda J Read, Sara Erickson, Allen G Harmsen
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    ABSTRACT: The mechanisms of the primary adaptive immune response to Coxiella burnetii are not well known. Following inoculation of the lungs with C. burnetii Nine Mile phase I (NMI), SCID mice developed pneumonia and splenomegaly and succumbed to infection, whereas wild-type mice cleared the infection by 24 days. SCID mice reconstituted with either CD4+ T cells or CD8+ T cells alone were able to control the infection, indicating that the presence of either type of T cells was sufficient to control infection, and B cells were not necessary for primary immunity. Similarly, wild-type mice depleted of either CD4+ T cells or CD8+ T cells controlled infections in their lungs, but these mice were highly susceptible if they were depleted of both types of T cells. However, compared to CD4+ T-cell-dependent protection, CD8+ T-cell-dependent protection resulted in less inflammation in the lungs and less growth of bacteria in the spleens.
    Infection and immunity 03/2010; 78(7):3019-26. · 4.21 Impact Factor
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    Quinton O King, Benfang Lei, Allen G Harmsen
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    ABSTRACT: We compared the growth of Streptococcus pneumoniae mutants with a disruption in the gene for either pneumococcal surface protein A (PspA-), neuraminidase A (NanA-), or hyaluronidase (Hyl-) to that of the parental strain D39 by means of a competitive growth model in mice with and those without prior influenza virus infection. The numbers of total bacteria recovered from mice with prior influenza virus infection were significantly greater than those recovered from mice without prior influenza virus infection. Although the Hyl- and NanA- mutants did not display attenuation in mice with or without prior influenza virus infection, the PspA- mutant exhibited attenuation both in mice with and in mice without prior influenza virus infection. This defect was severe in influenza virus-infected mice, for which growth of the PspA- mutant was 1800-fold lower than that of the parental strain D39. Furthermore, PspA immunization significantly reduced secondary bacterial lung burdens and concentrations of specific markers of lung damage in mice receiving serotypes 2, 3, and 4 pneumococci. Our findings indicate that PspA contributes to secondary S. pneumoniae infection after influenza virus infection and that PspA immunization mitigates early secondary pneumococcal lung infections.
    The Journal of Infectious Diseases 09/2009; 200(4):537-45. · 5.85 Impact Factor
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    ABSTRACT: Influenza virus infections increase susceptibility to secondary bacterial infections, such as pneumococcal pneumonia, resulting in increased morbidity and mortality. Influenza-induced tissue damage is hypothesized to increase susceptibility to Streptococcus pneumoniae infection by increasing adherence to the respiratory epithelium. Using a mouse model of influenza infection followed by S. pneumoniae infection, we found that an influenza infection does not increase the number of pneumococci initially present within the trachea, but does inhibit pneumococcal clearance by 2 hours after infection. To determine whether influenza damage increases pneumococcal adherence, we developed a novel murine tracheal explant system to determine influenza-induced tissue damage and subsequent pneumococcal adherence. Murine tracheas were kept viable ex vivo as shown by microscopic examination of ciliary beating and cellular morphology using continuous media flow for up to 8 days. Tracheas were infected with influenza virus for 0.5-5 days ex vivo, and influenza-induced tissue damage and the early stages of repair to the epithelium were assessed histologically. A prior influenza infection did not increase pneumococcal adherence, even when the basement membrane was maximally denuded or during the repopulation of the basement membrane with undifferentiated epithelial cells. We measured mucociliary clearance in vivo and found it was decreased in influenza-infected mice. Together, our results indicate that exposure of the tracheal basement membrane contributes minimally to pneumococcal adherence. Instead, an influenza infection results in decreased tracheal mucociliary velocity and initial clearance of pneumococci, leading to an increased pneumococcal burden as early as 2 hours after pneumococcal infection.
    American Journal of Respiratory Cell and Molecular Biology 07/2009; 42(4):450-60. · 4.15 Impact Factor
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    ABSTRACT: Destruction of the architectural and subsequently the functional integrity of the lung following pulmonary viral infections is attributable to both the extent of pathogen replication and to the host-generated inflammation associated with the recruitment of immune responses. The presence of antigenically disparate pulmonary viruses and the emergence of novel viruses assures the recurrence of lung damage with infection and resolution of each primary viral infection. Thus, there is a need to develop safe broad spectrum immunoprophylactic strategies capable of enhancing protective immune responses in the lung but which limits immune-mediated lung damage. The immunoprophylactic strategy described here utilizes a protein cage nanoparticle (PCN) to significantly accelerate clearance of diverse respiratory viruses after primary infection and also results in a host immune response that causes less lung damage. Mice pre-treated with PCN, independent of any specific viral antigens, were protected against both sub-lethal and lethal doses of two different influenza viruses, a mouse-adapted SARS-coronavirus, or mouse pneumovirus. Treatment with PCN significantly increased survival and was marked by enhanced viral clearance, accelerated induction of viral-specific antibody production, and significant decreases in morbidity and lung damage. The enhanced protection appears to be dependent upon the prior development of inducible bronchus-associated lymphoid tissue (iBALT) in the lung in response to the PCN treatment and to be mediated through CD4+ T cell and B cell dependent mechanisms. The immunoprophylactic strategy described utilizes an infection-independent induction of naturally occurring iBALT prior to infection by a pulmonary viral pathogen. This strategy non-specifically enhances primary immunity to respiratory viruses and is not restricted by the antigen specificities inherent in typical vaccination strategies. PCN treatment is asymptomatic in its application and importantly, ameliorates the damaging inflammation normally associated with the recruitment of immune responses into the lung.
    PLoS ONE 01/2009; 4(9):e7142. · 3.53 Impact Factor
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    ABSTRACT: Influenza-pseudotyped Gag virus-like particles (VLPs) were produced via the expression of influenza hemagglutinin (HA), neuraminidase (NA) and the murine leukemia virus Gag product in the baculovirus-insect cell expression system. Hemagglutination specific activities of sucrose gradient-purified VLPs were similar to those of egg-grown influenza viruses but particle morphologies were gamma retrovirus-like in the form of consistent 100nm spheres. Immunization of mice and ferrets demonstrated robust immunogenicity and protection from challenge with no measurable morbidity. Ferret data were striking in that immunization with H5N1 VLPs representing either A/Vietnam/1203/04 or A/Indonesia/5/05 resulted in solid protection against highly pathogenic A/Vietnam/1203/04 challenge with no detectable virus in the upper respiratory tract post-challenge in either group. H1N1 VLP immunization of ferrets resulted in partial protection against H5N1 challenge with markedly accelerated virus clearance from the upper respiratory tract relative to controls. The immunogenicity of influenza-pseudotyped VLPs was not dependent on the adjuvant properties of replication competent contaminating baculovirus. These data demonstrate robust vaccine protection of Gag-based, influenza-pseudotyped VLPs carrying a variety of influenza antigens and suggest applicability toward a number of additional respiratory viruses.
    Vaccine 12/2008; 27(4):530-41. · 3.49 Impact Factor
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    James A Wiley, Allen G Harmsen
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    ABSTRACT: In contrast to the detrimental outcomes most often associated with the resolution of coinfections, the model presented here involving a localized Pneumocystis infection of the lung, followed 2 wk later by an influenza virus infection, results in a significant beneficial outcome for the host. In the week following the influenza infection, immunocompetent coinfected animals exhibited an accelerated rate of virus clearance, an accelerated appearance of higher influenza-specific neutralizing Ab titers in their serum and bronchoalveolar lavage fluid (BALF), significantly reduced inflammatory cytokine levels in their BALF, and reduced levels of morbidity relative to animals infected only with influenza virus. The beneficial outcome observed in coinfected immunocompetent animals was dependent on the ongoing resolution of a viable Pneumocystis infection. No differences in viral clearance were detected between coinfected and influenza-only-infected muMT mice or likewise for SCID mice. The accelerated anti-influenza response did not appear to be associated with influenza-specific CD8 T cell-mediated responses or NK cell responses in the lung. Rather, the increased rate of viral clearance was due to the enhancement of the influenza-specific Ab response, which in turn was transiently dependent upon the resolution of the ongoing Pneumocystis infection.
    The Journal of Immunology 05/2008; 180(8):5613-24. · 5.52 Impact Factor
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    ABSTRACT: Improved treatment regimens have reduced fatalities from opportunistic diseases, such as Pneumocystis pneumonia, in AIDS patients. However, serious chronic conditions, including pulmonary hypertension (PH), are increasing in this group. We report here that when CD4 T cells in Pneumocystis-infected mice are temporally depleted and then allowed to return, the extended inflammation results in PH that persists after Pneumocystis is eliminated. Using this model of PH, we have found that i) the onset of PH is correlated with the return of CD4 T cells, but PH persists after CD4 levels diminish; ii) vascular remodeling accompanies PH, but whereas temporary medial hypertrophy is evident with transient PH in immunocompetent mice, persistent PH is associated with perivascular fibrosis; iii) elevated levels of the fibrotic mediator FIZZ1 are found in bronchoalveolar lavage fluid of mice with persistent PH; and iv) although Th2-related mechanisms may be involved in PH etiology, PH still occurs in interleukin-4 receptor-deficient mice under these conditions. Overall, the data presented here demonstrate that the immune response to an infectious disease pathogen, such as Pneumocystis, can, when perturbed and prolonged, lead to later development of a serious chronic condition such as PH.
    American Journal Of Pathology 10/2007; 171(3):790-9. · 4.60 Impact Factor
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    ABSTRACT: Tritrichomonas foetus is the cause of trichomoniasis in cattle. Severe infection is often associated with heavy neutrophil and macrophage accumulation, although it is not known how this response protects during early parasite colonization. The goal of this study was to examine the effects of an early host response upon initial T. foetus colonization within the murine reproductive tract. Mice depleted of neutrophils before T. foetus infection had a significantly higher parasite burden within the reproductive tract compared with mock-depleted control mice. Additionally, gp91(phox-/-)/ iNOS(-/-), and iNOS(-/-) mice had substantially larger parasite burdens than C57BL/6 control mice, whereas gp91l(Phox-/-) mice had similar parasite burden to C57BL/6 control mice. Interestingly, phorbol 12-myristate 13-acetate-stimulated neutrophils and macrophages isolated from all groups of mice were unable to kill T. foetus in vitro. However, macrophages isolated from gp91l(phox-/-) and C57BL/6 mice stimulated with interferon-gamma and lipopolysaccharide were able to kill T. foetus in vitro, whereas macrophages isolated from gp91(phox(-/-)/ iNOS(-/-) and iNOS(-/-) mice were unable to kill T. foetus, suggesting the ability of macrophages to produce reactive nitrogen species but not reactive oxygen species (ROS) is critical for parasite killing during early infection in vivo and in vitro. Additionally, neutrophils seem to control early dissemination of T. foetus throughout the reproductive tract, although production of ROS is not critical for this process.
    Journal of Parasitology 07/2007; 93(3):562-74. · 1.32 Impact Factor

Publication Stats

2k Citations
317.45 Total Impact Points

Institutions

  • 2002–2014
    • Montana State University
      • • Department of Microbiology
      • • Department of Immunology and Infectious Diseases
      Bozeman, Montana, United States
    • University of Rochester
      • Department of Pediatrics
      Rochester, NY, United States
  • 2012
    • University of Texas at San Antonio
      San Antonio, Texas, United States
  • 2009
    • Boston University
      • Pulmonary Center
      Boston, MA, United States
  • 2007
    • Dartmouth Medical School
      • Department of Microbiology and Immunology
      Hanover, NH, United States
  • 2001–2006
    • Trudeau Institute
      Saranac Lake, New York, United States
  • 2003
    • The Rockefeller University
      • Laboratory of Molecular Immunology
      New York City, New York, United States