LL-37), which is taken up by infected cells. Cathelicidin is one of well over
100 human antimicrobial peptides (AMP) that also include defensins, β-defensins,
lysozyme, lactoferrin, secretory leukocyte proteinase inhibitor, elafin, and RNase
7 (Hiemstra et al. 2016). Entry of bacteria and cathelicidin into the cell triggers
activation of the NLRP3 inflammasome and a cascade of events including the
activation of caspase 1, death of some infected cells, and release of the
pro-inflammatory cytokines IL-1β and IL-18. These events enhance inflammation
and recruit neutrophils. Under the influence of cathelicidin and other AMP, the
neutrophils form networks of extracellular fibres consisting mainly of DNA to which
some AMPs such as neutrophil elastase and cathepsin G adhere. These AMP-armed
Neutrophil Extracellular Traps (NET) contribute to inactivation of microorganisms
(Hiemstra et al. 2016).
18.4.4 Determine the Nature of the Microbial Environment
Data from the natural environment also inform each new individual’s immune
system about the balance and load of different types of organism in that individual’s
environment (Fig. 18.2). To take an extreme example, in tropical rainforest air,
fungal spores account for up to $45% of particulate matter, whereas this is not so in
modern urban environments (Elbert et al. 2007).
In general, Gram-negative bacteria are recognised by TLR4 that detects their
endotoxin (LPS), and Gram-positive organisms by NOD2, which recognises their
cell wall peptidoglycans, and by TLR2 which recognises many components including lipopeptides. However, TLR2 forms heterodimers with other TLR (notably
TLR1 and TLR6), and also recognises a vast range of molecules from bacteria,
viruses and protozoa, and perhaps even some forms of LPS. Bacteria are also
detected by human TLR8 and TLR7 which recognise single-stranded RNA. Expression of TLR7 is intracellular within airway epithelia and airway smooth muscle,
leading to secretion of pro-inflammatory cytokines and type-I IFNs (Dong et al.
2016). The air can also contain Archaea. These organisms do not seem to trigger
NOD2, TLR2, or TLR4, but their RNA, like that of bacteria, causes TLR8dependent inflammasome activation (Vierbuchen et al. 2017).
The fungal cell wall is quite different from that of bacteria or archaea, and
contains chitin (β-(1–4)-poly-N-acetyl-D-glucosamine; Ascomycota and
Basidiomycota) and chitosan (similar but partially de-acetylated; Zygomycota).
These are bound by numerous PRR, such as Fibrinogen C domain containing
1 (FIBCD1), RegIIIc, Toll-like receptor (TLR) 2, dectin-1, and the mannose receptor. Fungi also contain glucans that cross-link chitin or chitosan polymers that can be
recognised by dectin-1 (Camilli et al. 2018). We tend to forget the fungi because they
are not very numerous in the gut microbiota, but they are large organisms and so
constitute a significant fraction of the microbial bulk. It is likely that exposure to
greater loads of airborne fungi will therefore modulate the “farming” of the
340
G. A. W. Rook
100 human antimicrobial peptides (AMP) that also include defensins, β-defensins,
lysozyme, lactoferrin, secretory leukocyte proteinase inhibitor, elafin, and RNase
7 (Hiemstra et al. 2016). Entry of bacteria and cathelicidin into the cell triggers
activation of the NLRP3 inflammasome and a cascade of events including the
activation of caspase 1, death of some infected cells, and release of the
pro-inflammatory cytokines IL-1β and IL-18. These events enhance inflammation
and recruit neutrophils. Under the influence of cathelicidin and other AMP, the
neutrophils form networks of extracellular fibres consisting mainly of DNA to which
some AMPs such as neutrophil elastase and cathepsin G adhere. These AMP-armed
Neutrophil Extracellular Traps (NET) contribute to inactivation of microorganisms
(Hiemstra et al. 2016).
18.4.4 Determine the Nature of the Microbial Environment
Data from the natural environment also inform each new individual’s immune
system about the balance and load of different types of organism in that individual’s
environment (Fig. 18.2). To take an extreme example, in tropical rainforest air,
fungal spores account for up to $45% of particulate matter, whereas this is not so in
modern urban environments (Elbert et al. 2007).
In general, Gram-negative bacteria are recognised by TLR4 that detects their
endotoxin (LPS), and Gram-positive organisms by NOD2, which recognises their
cell wall peptidoglycans, and by TLR2 which recognises many components including lipopeptides. However, TLR2 forms heterodimers with other TLR (notably
TLR1 and TLR6), and also recognises a vast range of molecules from bacteria,
viruses and protozoa, and perhaps even some forms of LPS. Bacteria are also
detected by human TLR8 and TLR7 which recognise single-stranded RNA. Expression of TLR7 is intracellular within airway epithelia and airway smooth muscle,
leading to secretion of pro-inflammatory cytokines and type-I IFNs (Dong et al.
2016). The air can also contain Archaea. These organisms do not seem to trigger
NOD2, TLR2, or TLR4, but their RNA, like that of bacteria, causes TLR8dependent inflammasome activation (Vierbuchen et al. 2017).
The fungal cell wall is quite different from that of bacteria or archaea, and
contains chitin (β-(1–4)-poly-N-acetyl-D-glucosamine; Ascomycota and
Basidiomycota) and chitosan (similar but partially de-acetylated; Zygomycota).
These are bound by numerous PRR, such as Fibrinogen C domain containing
1 (FIBCD1), RegIIIc, Toll-like receptor (TLR) 2, dectin-1, and the mannose receptor. Fungi also contain glucans that cross-link chitin or chitosan polymers that can be
recognised by dectin-1 (Camilli et al. 2018). We tend to forget the fungi because they
are not very numerous in the gut microbiota, but they are large organisms and so
constitute a significant fraction of the microbial bulk. It is likely that exposure to
greater loads of airborne fungi will therefore modulate the “farming” of the
340
G. A. W. Rook