Rekha R. Rapaka

CD4+ T cell–independent DNA vaccination against opportunistic infections

Depletion or dysfunction of CD4+ T lymphocytes profoundly perturbs host defenses and impairs immunogenicity of vaccines. Here, we show that plasmid DNA vaccination with a cassette encoding antigen (OVA) and a second cassette encoding full-length CD40 ligand (CD40L), a molecule expressed on activated CD4+ T lymphocytes and critical for T cell helper function, can elicit significant titers of antigen-specific immunoglobulins in serum and Tc1 CD8+ T cell responses in CD4-deficient mice. To investigate whether this approach leads to CD4+ T cell-independent vaccine protection against a prototypic AIDS-defining infection, Pneumocystis (PC) pneumonia, we used serum from mice vaccinated with PC-pulsed, CD40L-modified DCs to immunoprecipitate PC antigens. Kexin, a PC antigen identified by this approach, was used in a similar DNA vaccine strategy with or without CD40L. CD4-deficient mice receiving DNA vaccines encoding Kexin and CD40L showed significantly higher anti-PC IgG titers as well as opsonic killing of PC compared with those vaccinated with Kexin alone. Moreover, CD4-depleted, Kexin-vaccinated mice showed a 3-log greater protection in a PC challenge model. Adoptive transfer of CD19+ cells or IgG to SCID mice conferred protection against PC challenge, indicating a role of humoral immunity in the protection. The results of these studies show promise for CD4-independent vaccination against HIV-related or other opportunistic pathogens.

Dectin-1 Fc Targeting of Aspergillus fumigatus Beta-Glucans Augments Innate Defense against Invasive Pulmonary Aspergillosis

ABSTRACT Invasive pulmonary aspergillosis (IPA) has significantly increased over the last decade. Here, a fusion protein consisting of the Dectin-1 extracellular domain linked to the Fc portion of murine immunoglobulin G1 augmented alveolar macrophage killing of Aspergillus fumigatus and shifted mortality associated with IPA via attenuation of A. fumigatus growth in the lung.

Pathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis: current understanding and future directions

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disease characterized clinically by wheezing, pulmonary infiltrates, bronchiectasis, and fibrosis that affects patients with asthma and cystic fibrosis (CF). Although this disease has been characterized by a Th2 immune response to Aspergillus, the disease has some features such as central bronchiectasis which is not seen in other Th2 driven lung diseases such as atopic asthma. Here we will review the current pathophysiology of ABPA in CF and highlight new molecules that may affect immune responses against Aspergillus and ABPA disease pathogenesis.

Enhanced Defense against Pneumocystis carinii Mediated by a Novel Dectin-1 Receptor Fc Fusion Protein

Pneumocystis carinii (PC) pneumonia is a leading opportunistic infection found among HIV-infected individuals worldwide. Although CD4+ T cell deficiency clearly correlates with susceptibility to PC pneumonia, murine models of disease indicate that PC-directed Abs may prevent infection and/or inhibit growth of existing PC within the lungs. Recognition of PC by alveolar macrophages involves the β-glucan receptor Dectin-1 and macrophage effector function against PC is enhanced by Abs derived from PC-vaccinated hosts. We developed a fusion protein consisting of the extracellular domain of Dectin-1 linked to the Fc portion of murine IgG1, which we hypothesized would enhance host recognition and opsonic phagocytosis of PC. The recombinant protein, Dectin-Fc, is dimeric and the Ag recognition site identifies β-1,3 glucan linkages specifically and with high affinity (KD = 2.03 × 10−7 M). Dectin-Fc enhances RAW264.7 macrophage recognition of the β-glucan containing particulate zymosan in an FcγRII- and FcγRIII-dependent manner and preopsonization of PC organisms with Dectin-Fc increased alveolar and peritoneal macrophage-dependent killing of PC. SCID mice treated with a replication incompetent adenoviral vector expressing Dectin-Fc had attenuated growth of PC within the lungs, overall decreased PC lung burden, and diminished correlates of PC-related lung damage relative to SCID mice receiving a control vector. These findings demonstrate that targeting PC β-glucan with Dectin-Fc enhances host recognition and clearance of PC in the absence of B and T cells, and suggest that FcγR-based targeting of PC, via cell wall carbohydrate recognition, may promote resistance against PC pneumonia in the immunodeficient host.

Corrigendum. CD4+ T cell-independent DNA vaccination against opportunistic infections.

Original citation: J Clin Invest. 2005;115(12):3536–3544. doi:10.1172/JCI26306. Citation for this corrigendum: J Clin Invest. 2015;125(3):1364. doi:10.1172/JCI81228. Karen A. Norris has requested to be removed from the author list, and the corresponding author has agreed. The revised author list is shown above.

Erratum: CD4+ T cell'independent DNA vaccination against opportunistic infections (Journal of Clinical Investigation (2005) 115: 12 (3536-3544) DOI: 10.1172/JCI26306)

Original citation: J Clin Invest. 2005;115(12):3536–3544. doi:10.1172/JCI26306. Citation for this corrigendum: J Clin Invest. 2015;125(3):1364. doi:10.1172/JCI81228. Karen A. Norris has requested to be removed from the author list, and the corresponding author has agreed. The revised author list is shown above.

CD4+ T cell–independent DNA vaccination against opportunisticinfections

Original citation: J Clin Invest. 2005;115(12):3536–3544. doi:10.1172/JCI26306. Citation for this corrigendum: J Clin Invest. 2015;125(3):1364. doi:10.1172/JCI81228. Karen A. Norris has requested to be removed from the author list, and the corresponding author has agreed. The revised author list is shown above.