Synchronized activation and refolding of influenza hemagglutinin in multimeric fusion machines

At the time of fusion, membranes are packed with fusogenic proteins. Do adjacent individual proteins interact with each other in the plane of the membrane? Or does each of these proteins serve as an independent fusion machine? Here we report that the low pH–triggered transition between the initial and final conformations of a prototype fusogenic protein, influenza hemagglutinin (HA), involves a preserved interaction between individual HAs. Although the HAs of subtypes H3 and H2 show notably different degrees of activation, for both, the percentage of low pH–activated HA increased with higher surface density of HA, indicating positive cooperativity. We propose that a concerted activation of HAs, together with the resultant synchronized release of their conformational energy, is an example of a general strategy of coordination in biological design, crucial for the functioning of multiprotein fusion machines

Reversible stages of the low-pH-triggered conformational change in influenza virus hemagglutinin

The refolding of the prototypic fusogenic protein hemagglutinin (HA) at the pH of fusion is considered to be a concerted and irreversible discharge of a loaded spring, with no distinct intermediates between the initial and final conformations. Here, we show that HA refolding involves reversible conformations with a lifetime of minutes. After reneutralization, low pH-activated HA returns from the conformations wherein both the fusion peptide and the kinked loop of the HA2 subunit are exposed, but the HA1 subunits have not yet dissociated, to a structure indistinguishable from the initial one in functional, biochemical and immunological characteristics. The rate of the transition from reversible conformations to irreversible refolding depends on the pH and on the presence of target membrane. Importantly, recovery of the initial conformation is blocked by the interactions between adjacent HA trimers. The existence of the identified reversible stage of refolding can be crucial for allowing multiple copies of HA to synchronize their release of conformational energy, as required for fusion

Hypersensitivity reactions to non-betalactam antibiotics in children: An extensive review

In contrast to hypersensitivity reactions (HSRs) to -lactam antibiotics in children, studies about HSR to non--lactam antibiotics (NBLAs) such as sulfonamides, macrolides, quinolones, and antituberculosis agents are scarce, and information is generally limited to case reports. The aim of this extensive review was to summarize our present knowledge on clinical characteristics, evaluation, and management of HSR to NBLAs in children based on the literature published between 1980 and 2013. NBLAs have been reported to induce a wide spectrum of HSRs from mild eruptions to severe, and sometimes fatal, systemic drug reactions, especially in some high-risk groups. The diagnosis relied upon history and remained unconfirmed by allergological tests in most of the cases. Obtaining a detailed history is valuable in the diagnosis of suspected reactions to NBLAs. Diagnostic in vivo and in vitro tests for NBLAs lack validation, which makes the diagnosis challenging. The definitive diagnosis of NBLA hypersensitivity frequently depends upon drug provocation tests. Studies including children showed that only 7.8 to 36% of suspected immediate and delayed HSRs to NBLAs could be confirmed by skin and/or provocation tests. Therefore, a standardized diagnostic approach and management strategy should be developed and employed for pediatric patients in the evaluation of suspected HSRs to NBLAs, some of which may be critical and unreplaceable in certain clinical situations. image </inline-graphi

Hypersensitivity reactions to non-betalactam antibiotics in children: an extensive review

In contrast to hypersensitivity reactions (HSRs) to β-lactam antibiotics in children, studies about HSR to non-β-lactam antibiotics (NBLAs) such as sulfonamides, macrolides, quinolones, and antituberculosis agents are scarce, and information is generally limited to case reports. The aim of this extensive review was to summarize our present knowledge on clinical characteristics, evaluation, and management of HSR to NBLAs in children based on the literature published between 1980 and 2013. NBLAs have been reported to induce a wide spectrum of HSRs from mild eruptions to severe, and sometimes fatal, systemic drug reactions, especially in some high-risk groups. The diagnosis relied upon history and remained unconfirmed by allergological tests in most of the cases. Obtaining a detailed history is valuable in the diagnosis of suspected reactions to NBLAs. Diagnostic in vivo and in vitro tests for NBLAs lack validation, which makes the diagnosis challenging. The definitive diagnosis of NBLA hypersensitivity frequently depends upon drug provocation tests. Studies including children showed that only 7.8 to 36% of suspected immediate and delayed HSRs to NBLAs could be confirmed by skin and/or provocation tests. Therefore, a standardized diagnostic approach and management strategy should be developed and employed for pediatric patients in the evaluation of suspected HSRs to NBLAs, some of which may be critical and unreplaceable in certain clinical situations