David E. Briles

Basophils enhance immunological memory responses

The cellular basis of immunological memory remains a controversial issue. Here we show that basophils bound large amounts of intact antigens on their surface and were the main source of interleukins 6 and 4 in the spleen and bone marrow after restimulation with a soluble antigen. Depletion of basophils resulted in a much lower humoral memory response and greater susceptibility of immunized mice to sepsis induced by Streptococcus pneumoniae. Adoptive transfer of antigen-reactive basophils significantly increased specific antibody production, and activated basophils, together with CD4+ T cells, profoundly enhanced B cell proliferation and immunoglobulin production. These basophil-dependent effects on B cells required interleukins 6 and 4 and increased the capacity of CD4+ T cells to provide B cell help. Thus, basophils are important contributors to humoral memory immune responses.

Immunology of tuberculosis

TB is a chronic, necrotizing infection caused by M. tuberculosis. The clinical manifestations of disease are the result of a balance between the host response and bacterial virulence. Cellular immunity is responsible for effective control of infection, but cytokines released during the process of cellular immunity may also cause harm to the host. Humoral immunity plays little part in protection against TB. Individuals with defective cellular immunity are much more susceptible to disease from M. tuberculosis and are more likely to have a disseminated form of TB.

CCL5 Modulates Pneumococcal Immunity and Carriage

Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Recently, it has been shown that genetic polymorphisms can result in diminished expression of CCL5, which results in increased susceptibility to and progression of infectious diseases. We show that CCL5, together with Th cytokine mRNA expression, is temporally up-regulated during pneumococcal carriage. To determine the contribution of CCL5 to pneumococcal surface antigen A-specific humoral and cellular pneumococcal immunity, mice were treated with anti-CCL5 or control Abs before and during Streptococcus pneumoniae strain EF3030-challenge for the initiation of carriage. CCL5 blockade resulted in a decrease of CD4+ and CD8+ T cells as well as CD11b+ cells in the spleen, cervical lymph node, lung, and nasopharyngeal associated lymphoid tissue during the recognition phase of the pneumococcal adaptive immune response. CCL5 blockade significantly reduced the Ag-specific IgG2a and IgG1 Abs in serum and IgA Ab levels in nasal washes. These decreases also corresponded to reductions in Ag-specific T cell (mucosal and systemic) responses. CCL5 inhibition resulted in decreasing the quantity of IL-4- and IFN-γ-secreting CD4+ T cells and increasing the number of Ag-specific IL-10-producing CD4+ T cells; these changes combined also corresponded with the transition from pneumococcal carriage to lethal pneumonia. These data suggest that CCL5 is an essential factor for the induction and maintenance of protective pneumococcal immunity.

Protection of the elderly from pneumococcal pneumonia with a protein-based vaccine?

Vaccines exist to protect children and adults from pneumococcal infection. The adult vaccine contains capsular polysaccharides from those pneumococci causing the vast majority of pneumococcal infection around the world. This vaccine is, however, poorly immunogenic and not as protective as would be desired. The vaccine for children is a seven-valent conjugate vaccine, which is highly protective against invasive infection and offers some protection against otitis media and pneumococcal carriage. The capsular types in the vaccine are not all appropriate for the developing world and the vaccine is too expensive for use in the developing world. As a result of these problems there have been extensive efforts to develop pneumococcal vaccines for adults and children based on cross-reactive protein antigens. The molecules used are in general virulence factors and the antibodies to them neutralize their function, thus reducing the virulence of the infecting bacteria. Studies in humans have revealed that the proteins studied are invariably immunogenic in humans, as at least low levels of antibody are seen following colonization or infection. Studies in mice have demonstrated that vaccines containing more than one of these virulence proteins are generally more protective than those involving just one. Proteins that have been studied the most in mice are pneumococcal surface protein A (PspA), PspC, PsaA, and pneumolysin. PspA has been used in human safety trials and was shown to elicit antibodies that can protect mice from otherwise fatal pneumococcal infections.

Pneumococcal proteins that may constitute the next generation vaccine for pneumococcal disease

Abstract Cross-reactive “common” pneumococcal antigens offer an attractive alternative, or complement, to polysaccharides and polysaccharide-protein conjugate vaccines. These common antigens should be protective against strains of a wider range of capsular types than can be achieved with conjugate vaccines. Common protein antigens would be expected to be highly immunogenic in young children and should be able to be manufactured relatively inexpensively using recombinant techniques. It is hoped that these antigens will lead to a vaccine(s) that could have application worldwide, even in the poorest developing countries where the rates of fatal pneumococcal disease in children are the highest.

Early Events in the Pathogenesis of Enteric Fever in Mice

Salmonella typhimurium is the best studied of the salmonella which cause mouse typhoid (enteric fever). The portal of entry of salmonella that cause enteric fevers in the mouse and in other species is normally oral. However, the organisms quickly enter the lymph and blood, and most of the organisms that survive blood clearance become lodged in the spleen and liver where they grow and cause disease (Carter and Collins, 1974; Carter and Collins, 1974). Although salmonella which cause enteric fevers have been described as facultative intracellular parasites that resides within macrophages, there is controversy over the major location of S. typhimurium multiplication in vivo (Benjamin, et al, 1990; Carroll et al, 1979; Dunlap et al, 1991; Guo et al, 1986; Schurr et al, 1989).

Genetic control of the susceptibility to bacterial infection

Genetic Control of the Susceptibility to Infection with Pathogenic Bacteria.- Genetic Approaches to the Study of Disease Resistance: with Special Emphasis on the Use of Recombinant Inbred Mice. With 2 Figures.- Influence of Host Genes on Resistance of Inbred Mice to Lethal Infection with Salmonella typhimurium. With 3 Figures.- Genetic Control of Resistance to Mycobacterial Infection. With 1 Figure.- Genetic Control of Resistance to Listeria Infection. With 2 Figures.- X-Linked Immune Deficiency (xid) of CBA/N Mice.- Genetic Control of the Susceptibility to Pneumococcal Infection. With 4 Figures.- Lps Gene Regulation of Mucosal Immunity and Susceptibility to Salmonella Infection in Mice. With 7 figures.- Genetic Determination of Bacterial Virulence, with Special Reference to Salmonella.