Michael J. Mina

Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality

Extra dividends from measles vaccine Vaccination against measles has many benefits, not only lifelong protection against this potentially serious virus. Mina et al. analyzed data collected since mass vaccination began in high-income countries when measles was common. Measles vaccination is associated with less mortality from other childhood infections. Measles is known to cause transient immunosuppression, but close inspection of the mortality data suggests that it disables immune memory for 2 to 3 years. Vaccination thus does more than safeguard children against measles; it also stops other infections taking advantage of measles-induced immune damage. Science, this issue p. 694 Preventing measles prevents immune memory damage and nonspecifically safeguards against many childhood infections. Immunosuppression after measles is known to predispose people to opportunistic infections for a period of several weeks to months. Using population-level data, we show that measles has a more prolonged effect on host resistance, extending over 2 to 3 years. We find that nonmeasles infectious disease mortality in high-income countries is tightly coupled to measles incidence at this lag, in both the pre- and post-vaccine eras. We conclude that long-term immunologic sequelae of measles drive interannual fluctuations in nonmeasles deaths. This is consistent with recent experimental work that attributes the immunosuppressive effects of measles to depletion of B and T lymphocytes. Our data provide an explanation for the long-term benefits of measles vaccination in preventing all-cause infectious disease. By preventing measles-associated immune memory loss, vaccination protects polymicrobial herd immunity.

JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function

Intestinal barrier function is regulated by epithelial tight junctions, structures that control paracellular permeability. JAM-A regulates epithelial permeability through association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.

Live Attenuated Influenza Vaccine Enhances Colonization of Streptococcus pneumoniae and Staphylococcus aureus in Mice

ABSTRACT Community interactions at mucosal surfaces between viruses, like influenza virus, and respiratory bacterial pathogens are important contributors toward pathogenesis of bacterial disease. What has not been considered is the natural extension of these interactions to live attenuated immunizations, and in particular, live attenuated influenza vaccines (LAIVs). Using a mouse-adapted LAIV against influenza A (H3N2) virus carrying the same mutations as the human FluMist vaccine, we find that LAIV vaccination reverses normal bacterial clearance from the nasopharynx and significantly increases bacterial carriage densities of the clinically important bacterial pathogens Streptococcus pneumoniae (serotypes 19F and 7F) and Staphylococcus aureus (strains Newman and Wright) within the upper respiratory tract of mice. Vaccination with LAIV also resulted in 2- to 5-fold increases in mean durations of bacterial carriage. Furthermore, we show that the increases in carriage density and duration were nearly identical in all aspects to changes in bacterial colonizing dynamics following infection with wild-type (WT) influenza virus. Importantly, LAIV, unlike WT influenza viruses, had no effect on severe bacterial disease or mortality within the lower respiratory tract. Our findings are, to the best of our knowledge, the first to demonstrate that vaccination with a live attenuated viral vaccine can directly modulate colonizing dynamics of important and unrelated human bacterial pathogens, and does so in a manner highly analogous to that seen following wild-type virus infection. IMPORTANCE Following infection with an influenza virus, infected or recently recovered individuals become transiently susceptible to excess bacterial infections, particularly Streptococcus pneumoniae and Staphylococcus aureus. Indeed, in the absence of preexisting comorbidities, bacterial infections are a leading cause of severe disease during influenza epidemics. While this synergy has been known and is well studied, what has not been explored is the natural extension of these interactions to live attenuated influenza vaccines (LAIVs). Here we show, in mice, that vaccination with LAIV primes the upper respiratory tract for increased bacterial growth and persistence of bacterial carriage, in a manner nearly identical to that seen following wild-type influenza virus infections. Importantly, LAIV, unlike wild-type virus, did not increase severe bacterial disease of the lower respiratory tract. These findings may have consequences for individual bacterial disease processes within the upper respiratory tract, as well as bacterial transmission dynamics within LAIV-vaccinated populations Following infection with an influenza virus, infected or recently recovered individuals become transiently susceptible to excess bacterial infections, particularly Streptococcus pneumoniae and Staphylococcus aureus. Indeed, in the absence of preexisting comorbidities, bacterial infections are a leading cause of severe disease during influenza epidemics. While this synergy has been known and is well studied, what has not been explored is the natural extension of these interactions to live attenuated influenza vaccines (LAIVs). Here we show, in mice, that vaccination with LAIV primes the upper respiratory tract for increased bacterial growth and persistence of bacterial carriage, in a manner nearly identical to that seen following wild-type influenza virus infections. Importantly, LAIV, unlike wild-type virus, did not increase severe bacterial disease of the lower respiratory tract. These findings may have consequences for individual bacterial disease processes within the upper respiratory tract, as well as bacterial transmission dynamics within LAIV-vaccinated populations

Live Attenuated Influenza Vaccine, But Not Pneumococcal Conjugate Vaccine, Protects Against Increased Density and Duration of Pneumococcal Carriage After Influenza Infection in Pneumococcal Colonized Mice

Secondary bacterial infections due to Streptococcus pneumoniae and Staphylococcus aureus, responsible for excess morbidity and mortality during influenza epidemics, are often preceded by excess bacterial density within the upper respiratory tract. Influenza and pneumococcal vaccines reduce secondary infections within the lungs; however, their effects on upper respiratory tract carriage remain unknown. We demonstrate that a live attenuated influenza vaccine significantly reduces pneumococcal growth and duration of carriage during subsequent influenza to levels seen in influenza-naive controls. No benefit was seen after pneumococcal conjugate vaccine. Our results suggest that live attenuated influenza vaccines may significantly reduce bacterial disease during influenza epidemics.

The role of influenza in the severity and transmission of respiratory bacterial disease

Infections with influenza viruses and respiratory bacteria each contribute substantially to the global burden of morbidity and mortality. Simultaneous or sequential infection with these pathogens manifests in complex and difficult-to-treat disease processes that need extensive antimicrobial therapy and cause substantial excess mortality, particularly during annual influenza seasons and pandemics. At the host level, influenza viruses prime respiratory mucosal surfaces for excess bacterial acquisition and this supports increased carriage density and dissemination to the lower respiratory tract, while greatly constraining innate and adaptive antibacterial defences. Driven by virus-mediated structural modifications, aberrant immunological responses to sequential infection, and excessive immunopathological responses, co-infections are noted by short-term and long-term departures from immune homoeostasis, inhibition of appropriate pathogen recognition, loss of tolerance to tissue damage, and general increases in susceptibility to severe bacterial disease. At the population level, these effects translate into increased horizontal bacterial transmission and excess use of antimicrobial therapies. With increasing concerns about future possible influenza pandemics, the past decade has seen rapid advances in our understanding of these interactions. In this Review, we discuss the epidemiological and clinical importance of influenza and respiratory bacterial co-infections, including the foundational efforts that laid the groundwork for todays investigations, and detail the most important and current advances in our understanding of the structural and immunological mechanisms underlying the pathogenesis of co-infection. We describe and interpret what is known in sequence, from transmission and phenotypic shifts in bacterial dynamics to the immunological, cellular, and molecular modifications that underlie these processes, and propose avenues of further research that might be most valuable for prevention and treatment strategies to best mitigate excess disease during future influenza pandemics.

Base deficit as a marker of survival after traumatic injury: Consistent across changing patient populations and resuscitation paradigms

BACKGROUND: Damage control resuscitation (DCR) has improved outcomes in severely injured patients. In civilian centers, massive transfusion protocols (MTPs) represent the most formal application of DCR principles, ensuring early, accurate delivery of high fixed ratios of blood components. Recent data suggest that DCR may also help address early trauma-induced coagulopathy. Finally, base deficit (BD) is a long-recognized and simple early prognostic marker of survival after injury. METHODS: Outcomes of patients with admission BD data resuscitated during the DCR era (2007–2010) were compared with previously published data (1995–2003) of patients cared for before the DCR era (pre-DCR). Patients were considered to have no hypoperfusion (BD, >−6), mild (BD, −6 to −14.9), moderate (BD, −15 to −23.9), or severe hypoperfusion (BD, <−24). RESULTS: Of 6,767 patients, 4,561 were treated in the pre-DCR era and 2,206 in the DCR era. Of the latter, 218 (9.8%) represented activations of the MTP. DCR patients tended to be slightly older, more likely victims of penetrating trauma, and slightly more severely injured as measured by trauma scores and BD. Despite these differences, overall survival was unchanged in the two eras (86.4% vs. 85.7%, p = 0.67), and survival curves stratified by mechanism of injury were nearly identical. Patients with severe BD who were resuscitated using the MTP, however, experienced a substantial increase in survival compared with pre-DCR counterparts. CONCLUSION: Despite limited adoption of formal DCR, overall survival after injury, stratified by BD, is identical in the modern era. Patients with severely deranged physiology, however, experience better outcomes. BD remains a consistent predictor of mortality after traumatic injury. Predicted survival depends more on the energy level of the injury (stab wound vs. nonstab wound) than the mechanism of injury (blunt vs. penetrating). LEVEL OF EVIDENCE: IV, therapeutic/prognostic study.

A live-attenuated pneumococcal vaccine elicits CD4+ T-cell dependent class switching and provides serotype independent protection against acute otitis media

Acute otitis media (AOM) caused by Streptococcus pneumoniae remains one of the most common infectious diseases worldwide despite widespread vaccination. A major limitation of the currently licensed pneumococcal vaccines is the lack of efficacy against mucosal disease manifestations such as AOM, acute bacterial sinusitis and pneumonia. We sought to generate a novel class of live vaccines that (1) retain all major antigenic virulence proteins yet are fully attenuated and (2) protect against otitis media. A live vaccine candidate based on deletion of the signal recognition pathway component ftsY induced potent, serotype‐independent protection against otitis media, sinusitis, pneumonia and invasive pneumococcal disease. Protection was maintained in animals coinfected with influenza virus, but was lost if mice were depleted of CD4+ T cells at the time of vaccination. The live vaccine induced a strong serum IgG2a and IgG2b response that correlated with CD4+ T‐cell mediated class switching. Deletion of genes required for microbial adaptation to the host environment is a novel live attenuated vaccine strategy yielding the first experimental vaccine effective against pneumococcal otitis media.

The potential impact of coinfection on antimicrobial chemotherapy and drug resistance

Across a range of pathogens, resistance to chemotherapy is a growing problem in both public health and animal health. Despite the ubiquity of coinfection, and its potential effects on within-host biology, the role played by coinfecting pathogens on the evolution of resistance and efficacy of antimicrobial chemotherapy is rarely considered. In this review, we provide an overview of the mechanisms of interaction of coinfecting pathogens, ranging from immune modulation and resource modulation, to drug interactions. We discuss their potential implications for the evolution of resistance, providing evidence in the rare cases where it is available. Overall, our review indicates that the impact of coinfection has the potential to be considerable, suggesting that this should be taken into account when designing antimicrobial drug treatments.

Pathogen Replication, Host Inflammation, and Disease in the Upper Respiratory Tract

Whole-genome assemblies of 19 placental mammals and two outgroup species were used to reconstruct the order and orientation of syntenic fragments in chromosomes of the eutherian ancestor and six other descendant ancestors leading to human. For ancestral chromosome reconstructions, we developed an algorithm (DESCHRAMBLER) that probabilistically determines the adjacencies of syntenic fragments using chromosome-scale and fragmented genome assemblies. The reconstructed chromosomes of the eutherian, boreoeutherian, and euarchontoglires ancestor each included >80% of the entire length of the human genome, whereas reconstructed chromosomes of the most recent common ancestor of simians, catarrhini, great apes, and humans and chimpanzees included >90% of human genome sequence. These high-coverage reconstructions permitted reliable identification of chromosomal rearrangements over ∼105 My of eutherian evolution. Orangutan was found to have eight chromosomes that were completely conserved in homologous sequence order and orientation with the eutherian ancestor, the largest number for any species. Ruminant artiodactyls had the highest frequency of intrachromosomal rearrangements, and interchromosomal rearrangements dominated in murid rodents. A total of 162 chromosomal breakpoints in evolution of the eutherian ancestral genome to the human genome were identified; however, the rate of rearrangements was significantly lower (0.80/My) during the first ∼60 My of eutherian evolution, then increased to greater than 2.0/My along the five primate lineages studied. Our results significantly expand knowledge of eutherian genome evolution and will facilitate greater understanding of the role of chromosome rearrangements in adaptation, speciation, and the etiology of inherited and spontaneously occurring diseases.

Let technology do the work: Improving prediction of massive transfusion with the aid of a smartphone application

BACKGROUND The use of massive transfusion protocols (MTPs) is now common in civilian trauma settings, and early activation of MTP has been shown to increase survival of MTP recipients. Numerous MTP prediction tools have been developed; however, they are often cumbersome to use efficiently or have traded predictive power for ease of use. We hypothesized that a highly accurate predictor of massive transfusion could be created and incorporated into a smartphone application that would provide an additional tool for clinicians to use in directing the resuscitation of critically injured patients. METHODS Data from all trauma admissions since the inception of MTP were put in place at Grady Memorial Hospital in Atlanta, Georgia, were collected. A predictive model was developed using the least absolute shrinkage and selection operator (LASSO) and 10-fold cross validation. Data were resampled over 500 iterations, each using a unique and random subset of 80% of the data for model training and 20% for validation. RESULTS The trauma registry contained 13,961 cases between 2007 and November 2011, of which 10,900 were complete and 394 received MTP. Of 44 input terms, only the mechanism of injury, heart rate, systolic blood pressure, and base deficit were found to be important predictors of massive transfusion. Our model has an area under the receiver operating curve of 0.96 (against data not used during model training) and accurately predicted MTP status for 97% of all patients. The model accurately discriminated full MTPs from MTP activations that did not meet criteria for massive transfusion. While complex to calculate by hand, our model has been packaged into a mobile application, allowing for efficient use while minimizing potential for user error. CONCLUSION We have developed a highly accurate model for the prediction of massive transfusion that has potential to be easily accessed and used within a simple and efficient mobile application for smartphones. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.