In cancer patients undergoing radiation therapy, the beneficial effects of radiation can extend beyond direct cytotoxicity to tumor cells. Delivery of localized radiation to tumors often leads to systemic responses at distant sites, a phenomenon known as the abscopal effect which has been attributed to the induction and enhancement of the endogenous anti-tumor innate and adaptive immune response. The mechanisms surrounding the abscopal effect are diverse and include trafficking of lymphocytes into the tumor microenvironment, enhanced tumor recognition and killing via up-regulation of tumor antigens and antigen presenting machinery and, induction of positive immunomodulatory pathways. Here, we discuss potential mechanisms of radiation-induced enhancement of the anti-tumor response through its effect on the host immune system and explore potential combinational immune-based strategies such as adoptive cellular therapy using ex vivo expanded NK and T cells as a means of delivering a potent effector population in the context of radiation-enhanced anti-tumor immune environment.
Nasal colonization by Staphylococcus aureus is a major predisposing factor for subsequent infection. Recent reports of increased S. aureus colonization among children receiving pneumococcal vaccine implicate Streptococcus pneumoniae as an important competitor for the same niche. Since S. pneumoniae uses H 2 O 2 to kill competing bacteria, we hypothesized that oxidant defense could play a significant role in promoting S. aureus colonization of the nasal mucosa. Using targeted mutagenesis, we showed that S. aureus expression of catalase contributes significantly to the survival of this pathogen in the presence of S. pneumoniae both in vitro and in a murine model of nasal cocolonization.Staphylococcus aureus causes a wide range of infections ranging from minor skin infections to life-threatening invasive diseases. The emergence of methicillin-resistant strains with high virulence potential in both hospital and community settings is contributing to a current public health crisis (9, 12, 13).A major risk factor for S. aureus infection is antecedent colonization of the nasal mucosa (19). Successful colonization depends not only on the ability of S. aureus to survive host factors (4, 6) but also on coexistence with other bacteria (16,21).The latter concept has been underscored by two recent reports that implicate Streptococcus pneumoniae as a primary competitor for niche colonization (3,15).Specifically, one surveillance study performed in an area where pneumococcal vaccination was not practiced showed that the S. pneumoniae carriage rate in children was negatively associated with S. aureus nasal carriage (15). The other study showed that children with recurrent otitis media vaccinated with the 7-valent pneumococcal vaccine had an increased incidence of S. aureus-related acute otitis media and S. aureus colonization after vaccination (3), suggesting that there is a natural competition for colonization between S. aureus and S. pneumoniae.S. pneumoniae produces H 2 O 2 as an antimicrobial factor to reduce competition by other upper respiratory pathogens, such as Haemophilus influenzae, Neisseria meningitides, Moraxella catarrhalis, and S. aureus (14, 16). Since S. aureus is a natural colonizer of the human nares, we hypothesized that its success derives in part from a relative resistance to H 2 O 2 killing by other microflora. Here we tested this hypothesis by generating a catalase knockout mutant strain of S. aureus and examining the role of enzymatic H 2 O 2 inactivation in niche competition with S. pneumoniae. MATERIALS AND METHODSBacterial strains, media, and mice. S. aureus strains were cultured at 37°C in Todd-Hewitt broth (THB) or on Todd-Hewitt agar (THA) (Difco). S. pneumoniae TIGR4 was cultured in THB with 0.5% yeast extract (THY) at 37°C in a 5% CO 2 incubator. Eight-to 10-week old female CD1 mice were purchased from Charles River Laboratories, Wilmington, MA. When included, antibiotics were added at the following concentrations: 100 g ampicillin/ml, 50 g erythromycin/ml, and 100 g spectinomycin/ml.Generation ...
Methicillin-resistant S. aureus emerged in recent decades to become a leading cause of infection worldwide. Colonization with MRSA predisposes to infection and facilitates transmission of the pathogen; however, available regimens are ineffective at preventing MRSA colonization. Studies of human nasal flora suggest that resident bacteria play a critical role in limiting S. aureus growth, and prompted us to query whether application of commensal resident bacteria could prevent nasal colonization with MRSA. We established a murine model system to study this question, and showed that mice nasally pre-colonized with S. epidermidis became more resistant to colonization with MRSA. Our study suggests that application of commensal bacteria with antibiotics could represent a more effective strategy to prevent MRSA colonization.
Recent emergence of methicillin-resistant Staphylococcus aureus both within and outside healthcare settings has accelerated the use of once reserved last line antibiotics such as vancomycin. With increased use of antibiotics, there has been a rapid rise in the rate of resistance development to the anti-MRSA drugs. As the antibiotic pipeline becomes strained, alternative strategies are being sought for future treatment of S. aureus. Here, we review several novel anti-staphylococcal strategies that, unlike conventional antibiotics, do not target essential gene products elaborated by the pathogen. The approaches seek instead to weaken the S. aureus defense by neutralizing its virulence factors or boosting host immunity. Other strategies target commensal bacteria that naturally colonize the human host to inhibit S. aureus colonization. Ultimately, the aim is to shift the balance between host defense and pathogen virulence in favor of inhibition of S. aureus pathogenic activities.
We recently identified two loci, mel1 and mel2, that affect macrophage infection by Mycobacterium marinum. The ability of these loci to confer enhanced infection in trans is presumably due to gene dosage effects since their presence on plasmids increases expression from five-to eightfold. Reasoning that this phenomenon would allow identification of other mycobacterial genes involved in macrophage infection, we conducted a screen of an M. marinum DNA library that provides 2.6-fold coverage of the entire genome for clones that affect macrophage infection. Our preliminary screen identified 76 plasmids that carry loci affecting macrophage infection. We eliminated plasmids that do not confer the expected phenotype when retransformed (70%), that have identical physical maps (5%), or that carry either of the mel1 or mel2 loci (14%) from further consideration. Four loci that confer enhanced infection (mel) and four that confer repressed infection (mrl) of macrophages were identified, and two of each group were chosen for detailed analysis. Saturating transposon mutagenesis was used to identify the loci responsible, and M. marinum mutants were constructed in the genes involved. We expect these genes to provide insight into how mycobacteria parasitize macrophages, an important component of innate immunity.Mycobacterium marinum is a natural pathogen of humans (41, 49, 57), fish, and amphibians (18), causing more than 150 human infections each year in the United States alone (29). Although M. marinum causes primarily skin lesions on the extremities in humans (19), it causes a systemic tuberculous disease in fish and amphibians (30,73,101). M. marinum infections result in granuloma formation, whether in humans, mice, fish, or amphibians (18)(19)(20)101). Granuloma formation occurs because macrophages become infected and allow growth of M. marinum during disease (19, 74) and in laboratory model systems (7,33,69,81). These characteristics of infections, along with the relative ease of manipulation (3,37,82,88), rapid growth rate compared to other pathogenic mycobacteria (18), and the presence of numerous useful virulence models (11,20,27,33,84,89,92), have aroused great interest in the molecular mechanisms of M. marinum pathogenesis. Significant progress has been made toward understanding M. marinum evolution (106), trafficking (7,86,98), secretion (1, 36), gene regulation (6, 82), photochromogenicity (35, 83), cell wall synthesis (3, 24, 37), granuloma formation (23, 27, 97), resistance to oxidative species (78,79,95,96), and mechanisms of macrophage infection (32, 38, 66).As a means to better understand the molecular mechanisms of macrophage infection by M. marinum, we recently screened a genomic library for loci that have the ability to confer enhanced macrophage infection to M. smegmatis (32), a nonpathogenic mycobacterial species that does not infect macrophages efficiently. We identified two M. marinum loci, mel1 and mel2, that confer enhanced macrophage infection to both M. smegmatis and M. marinum. The phenotypic effec...
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