Review Novel Therapies for Pneumonia-Associated Severe Asthma Phenotypes Angelica Papanicolaou, 1 Hao Wang, 1 Catherine Satzke, 2,3,4 Ross Vlahos, 1 Nick Wilson, 5 and Steven Bozinovski 1, * Distinct asthma phenotypes are emerging from well-defined cohort studies and appear to be associated with a history of pneumonia. Asthmatics are more susceptible to infections caused by Streptococcus pneumoniae; however, the mechanisms that underlie defective immunity to this pathogen are still being elucidated. Here, we discuss how alternatively activated macrophages (AAMs) in asthmatics are defective in bacterial phagocytosis and how respiratory viruses dis- rupt essential host immunity to cause bacterial dispersion deeper into the lungs. We also describe how respiratory pathogens instigate neutrophilic inflammation and amplify type-2 inflammation in asthmatics. Finally, we propose novel dual-acting strategies including granulocyte-colony-stimulating factor receptor (G-CSFR) antagonism and specialised pro-resolving mediators (SPMs) to suppress type-2 and neutrophilic inflammation without compromising pathogen clearance. The Link between Pneumococcal Pneumonia and Asthma Asthma is a chronic airway inflammatory disease that affects over 300 million people worldwide [1]. Typically, the airways in asthmatic patients have pathological levels of airway remodelling that leads to variable and reversible airflow obstruction manifesting as bronchial hyperresponsiveness [2]. These pathologies are classically driven by a dominant CD4 + T-helper type-2 (Th2) inflammatory response commonly caused by exposures to aeroallergens such as house dust mites (HDMs) [3]. The release of type-2 inflammatory cytokines, such as IL-4 and IL-13, mediates B cell isotype switching to IgE and triggers goblet cell metaplasia. IL-5 also potently facilitates eosinophil activa- tion and migration into the lungs [2]. It is also clear that the risk of developing pneumococcal pneu- monia is increased in asthmatics of all ages [4,5]. Compared with healthy individuals, the risk of hospitalisation by pneumonia is two to four times higher in asthmatics; severe asthmatics are at even greater risk [6]. This could reflect that Streptococcus pneumoniae (the pneumococcus, Spn) oropharyngeal carriage is increased in both adults and children with asthma [7,8]. Moreover, it remains largely unknown whether Spn vaccines adequately protect asthmatics from pneumonia [9]. Over the past decade, several studies have investigated the interaction between pathogenic bacteria and allergic airways disease. Spn is a Gram-positive respiratory pathogen and major cause of several human infections including otitis media, pneumonia, bacteraemia, and meningitis. Pneumococcal colonisation of the upper respiratory tract occurs commonly in children (over 90% in some low- and middle- income countries) [10], and is considered indispensable for both the spread and commencement of disease [11]. Following dissemination from the nasopharynx, Spn may enter the lower respiratory tract and cause pneumonia [12]. Globally, pneumonia is responsible for 15% of child mortality under 5 years of age, where the pneumococcus remains the most common bacterial cause i . Other key susceptible groups include the elderly and people with chronic respiratory diseases such as asthma [13]. In this review, we discuss why asthmatics are at heightened risk of developing serious pneumococcal infections including pneumonia [5]. Highlights Streptococcus pneumoniae is a lead- ing global cause of pneumonia. While asthma is now recognised as a het- erogeneous disease, people with se- vere asthma are fourfold more likely to develop pneumonia. Pneumococcal nasopharyngeal carriage and viral infections frequently coexist in asthmatics. Respiratory viruses will cause bacterial dispersion deeper into the lower airways to cause pneumonia. Type-2 inflammation results in the emer- gence of alternatively activated macro- phages in asthma that are defective at phagocytosing bacteria, which can per- mit the establishment of lower respiratory tract infections. Excessive neutrophilic inflammation is an inflammatory feature of both pneumonia and severe asthma. Novel therapies that target both neutrophils and type-2 inflam- mation have the potential to improve the pathological features of severe asthma. 1 Chronic Infectious and Inflammatory Disease Research Program, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia 2 Infection and Immunity, Murdoch Children's Research Institute, Parkville, VIC, Australia 3 Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia 4 Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia 5 CSL Limited, Parkville, VIC, Australia *Correspondence: steven.bozinovski@rmit.edu.au (S. Bozinovski). Trends in Molecular Medicine, Month 2020, Vol. xx, No. xx https://doi.org/10.1016/j.molmed.2020.07.006 1 © 2020 Elsevier Ltd. All rights reserved. Trends in Molecular Medicine TRMOME 1589 No. of Pages 12