Marine Actinomycetes, New Sources of Biotechnological Products.

The Actinomycetales order is one of great genetic and functional diversity, including diversity in the production of secondary metabolites which have uses in medical, environmental rehabilitation, and industrial applications. Secondary metabolites produced by actinomycete species are an abundant source of antibiotics, antitumor agents, anthelmintics, and antifungals. These actinomycete-derived medicines are in circulation as current treatments, but actinomycetes are also being explored as potential sources of new compounds to combat multidrug resistance in pathogenic bacteria. Actinomycetes as a potential to solve environmental concerns is another area of recent investigation, particularly their utility in the bioremediation of pesticides, toxic metals, radioactive wastes, and biofouling. Other applications include biofuels, detergents, and food preservatives/additives. Exploring other unique properties of actinomycetes will allow for a deeper understanding of this interesting taxonomic group. Combined with genetic engineering, microbial experimental evolution, and other enhancement techniques, it is reasonable to assume that the use of marine actinomycetes will continue to increase. Novel products will begin to be developed for diverse applied research purposes, including zymology and enology. This paper outlines the current knowledge of actinomycete usage in applied research, focusing on marine isolates and providing direction for future research.

Maternal vaccination: shaping the neonatal response to pertussis.

Antepartum maternal vaccination can protect highly sensitive newborns before they are old enough to receive their own vaccines. Two vaccines are currently recommended during pregnancy: the flu vaccine and the Tdap vaccine against tetanus, diphtheria, and pertussis. Although there is strong evidence that maternal vaccination works to protect the offspring, limitations in the understanding of vaccines and of maternal transfer of immunity compound to obscure our understanding of how they work. Here we focus on the example of pertussis to explore the possible mechanisms involved in the transfer of protection to offspring and how these may impact the newborn's response to future exposure to pertussis. For example, Tdap vaccines induce pathogen specific antibodies, and those antibodies are known to be transferred from mother to the fetus in utero and to the newborn via milk. But antibodies alone have modest impact on pertussis disease, and even less effect on colonization/transmission. Maternal immune cells can also be transferred to offspring and may play a direct role in protection from disease and/or influence the developing neonatal immune system. However, some of the transferred immunity may also blunt the offspring's response to subsequent vaccination. In this review we will summarize the protection conferred to offspring by maternal vaccination against pertussis and the likely mechanisms by which protection is transferred, identifying the many knowledge gaps that limit our most effective application of this approach.

Generating enhanced mucosal immunity against Bordetella pertussis: current challenges and new directions.

Bordetella pertussis (Bp) is the highly transmissible etiologic agent of pertussis, a severe respiratory disease that causes particularly high morbidity and mortality in infants and young children. Commonly known as "whooping cough," pertussis is one of the least controlled vaccine-preventable diseases worldwide with several countries experiencing recent periods of resurgence despite broad immunization coverage. While current acellular vaccines prevent severe disease in most cases, the immunity they confer wanes rapidly and does not prevent sub clinical infection or transmission of the bacterium to new and vulnerable hosts. The recent resurgence has prompted new efforts to generate robust immunity to Bp in the upper respiratory mucosa, from which colonization and transmission originate. Problematically, these initiatives have been partially hindered by research limitations in both human and animal models as well as potent immunomodulation by Bp. Here, we consider our incomplete understanding of the complex host-pathogen dynamics occurring in the upper airway to propose new directions and methods that may address critical gaps in research. We also consider recent evidence that supports the development of novel vaccines specifically designed to generate robust mucosal immune responses capable of limiting upper respiratory colonization to finally halt the ongoing circulation of Bordetella pertussis.

Novel murine model reveals an early role for pertussis toxin in disrupting neonatal immunity to Bordetella pertussis.

The increased susceptibility of neonates to specific pathogens has previously been attributed to an underdeveloped immune system. More recent data suggest neonates have effective protection against most pathogens but are particularly susceptible to those that target immune functions specific to neonates. Bordetella pertussis (Bp), the causative agent of "whooping cough", causes more serious disease in infants attributed to its production of pertussis toxin (PTx), although the neonate-specific immune functions it targets remain unknown. Problematically, the rapid development of adult immunity in mice has confounded our ability to study interactions of the neonatal immune system and its components, such as virtual memory T cells which are prominent prior to the maturation of the thymus. Here, we examine the rapid change in susceptibility of young mice and define a period from five- to eight-days-old during which mice are much more susceptible to Bp than mice even a couple days older. These more narrowly defined "neonatal" mice display significantly increased susceptibility to wild type Bp but very rapidly and effectively respond to and control Bp lacking PTx, more rapidly even than adult mice. Thus, PTx efficiently blocks some very effective form(s) of neonatal protective immunity, potentially providing a tool to better understand the neonatal immune system. The rapid clearance of the PTx mutant correlates with the early accumulation of neutrophils and T cells and suggests a role for PTx in disrupting their accumulation. These results demonstrate a striking age-dependent response to Bp, define an early age of extreme susceptibility to Bp, and demonstrate that the neonatal response can be more efficient than the adult response in eliminating bacteria from the lungs, but these neonatal functions are substantially blocked by PTx. This refined definition of "neonatal" mice may be useful in the study of other pathogens that primarily infect neonates, and PTx may prove a particularly valuable tool for probing the poorly understood neonatal immune system.

Adaptive immune protection of the middle ears differs from that of the respiratory tract.

The efficacy of the adaptive immune system in the middle ear (ME) is well established, but the mechanisms are not as well defined as those of gastrointestinal or respiratory tracts. While cellular elements of the adaptive response have been detected in the MEs following infections (or intranasal immunizations), their specific contributions to protecting the organ against reinfections are unknown. How immune protection mechanisms of the MEs compares with those in the adjacent and attached upper and lower respiratory airways remains unclear. To address these knowledge gaps, we used an established mouse respiratory infection model that we recently showed also involves ME infections. Bordetella bronchiseptica delivered to the external nares of mice in tiny numbers very efficiently infects the respiratory tract and ascends the Eustachian tube to colonize and infect the MEs, where it causes severe but acute inflammation resembling human acute otitis media (AOM). Since this AOM naturally resolves, we here examine the immunological mechanisms that clear infection and protect against subsequent infection, to guide efforts to induce protective immunity in the ME. Our results show that once the MEs are cleared of a primary B. bronchiseptica infection, the convalescent organ is strongly protected from reinfection by the pathogen despite its persistence in the upper respiratory tract, suggesting important immunological differences in these adjacent and connected organs. CD4+ and CD8+ T cells trafficked to the MEs following infection and were necessary to robustly protect against secondary challenge. Intranasal vaccination with heat killed B. bronchiseptica conferred robust protection against infection to the MEs, even though the nasopharynx itself was only partially protected. These data establish the MEs as discrete effector sites of adaptive immunity and shows that effective protection in the MEs and the respiratory tract is significantly different. This model system allows the dissection of immunological mechanisms that can prevent bacteria in the nasopharynx from ascending the ET to colonize the ME.