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ity of SPRR2A, as determined in vitro, in-

cludes low salt concentrations and an acidic

pH. These are the exact conditions found in

the small intestine, tying together the au-

thors in vitro and in vivo observations.

The production of SPRR2A is also elicited

by the type 2 cytokines interleukin-4 (IL-4)

and IL-13, which are typically produced in

response to helminth infection as part of a

protective type 2 immune response. Given

the number of known AMPs, it is not sur-

prising that an additional family member

has been discovered. But the finding that

SPRR2A production can be enhanced by

IL-4 and IL-13 renders SPRR2A distinct

among the known AMPs.

The relevance of this cytokine-mediated

induction of SPRR2A is demonstrated when

mice genetically deficient for SPRR2A are

exposed to the helminth Heligmosomoides

polygyrus, a model of mammalian intestinal

helminth infection. SPRR2A does not affect

the ability of H. polygyrus to infect the host

but instead protects infected mice from

bacterial invasion across the epithelial

barrier following its damage by the helminth

(see the figure). In a normal situation, the

host responds to this damage through

an IL-4 and IL-13–dependent increase in

SPRR2A expression by the epithelial cells.

This in turn leads to the elimination of

Gram-positive bacteria in close proximity

to the epithelium, thereby preventing

their translocation across the damaged

epithelium and into the underlying tissues.

Although the consequences of bacterial

entry into the tissue following helminth

infection were not examined, it is likely this

would result in increased intestinal, and

possibly even systemic, inflammation. This

suggests that there is an innate drive for the

host to heighten its defenses against bacte-

rial infection during intestinal helminth in-

fection. One major benefit of this response

is the ability to curb the onset of a concur-

rent helminth and bacterial infection that

could overwhelm the host immune response.

Notably, this reveals that a close evolution-

ary relationship exists between the mamma-

lian host, helminth, and intestinal bacteria.

A plethora of recent studies reveal that

helminths can shape the intestinal bacte-

rial microbiota ( 4 ), with helminth–bacterial

cross-talk able to modulate host resistance

against future infection with the same para-

site ( 5 ) and the development of inflammatory

diseases such as allergy ( 6 ) and inflammatory

bowel disease (IBD) ( 7 ). Hu et al. also found

SPRR2A gene expression in biopsies taken

from the large intestine of IBD patients.

However, whether SPRR2A plays a protec-

tive or pathological role in IBD remains

unknown. Helminth-associated changes to

microbial composition have been repeat-

edly linked to host production of the type

2 cytokines IL-4 and IL-13 ( 4 ), yet the exact

mechanisms remain unclear. Considering the

findings of Hu et al., it is likely that SPRR2A

represents one such mechanism, and there

are likely to be more.

Hu et al. found that two common residents

of the mammalian intestine, helminths and

bacteria, can independently lead to expres-

sion of SPRR2A by the intestinal epithe-

lium. This raises the question of whether

other common intestinal pathogens, such

as viruses or protozoa, also drive SPRR2A

expression. If so, further studies may reveal

a role for SPRR2A in preventing bacterial

invasion during such infections—akin to its

role in helminth infection. The authors also

noted SPRR2A gene expression in healthy

esophagus and bladder, two other sites that

commonly interface with microbes from the

environment. Although the implications of

this finding are not clear, it is compelling

to consider that while the epithelia of these

tissues differ markedly in terms of struc-

ture, they must both constantly adapt to

physical alterations such as the mechani-

cal distension caused by food or urine. In

keeping with this, SPRR proteins have pre-

viously been postulated to contribute to the

mechanical properties of the skin epithe-

lium ( 8 ). Whether SPRR2A plays a role in

tissue adaption to mechanical stress and/

or resistance to bacterial infection in the

esophagus and bladder deserves further

attention. This is especially relevant to the

bladder, with urinary tract infections by

the Gram-positive bacteria Staphylococcus

saprophyticus, Enterococcus faecalis, and

Streptococcus agalactiae common in cer-

tain demographic groups, such as pregnant

women and the elderly ( 9 ). Future studies

exploring the specific role of SPRR2A across

different diseases and in different groups

may reveal additional functions of SPRR2A.

Some of the most important immunologi-

cal discoveries have been made from research

based on careful observation of natural im-

mune phenomena that take place during

health, disease, or infection. The findings of

Hu et al. highlight the potential for discovery

of unknown pathways through evaluation

of the complex interplay that occurs during

transkingdom interactions in the mamma-

lian intestine. j

REFERENCES AND NOTES

1. L. J. Zhang, R. L. Gallo, Curr. Biol. 26 , R14 (2016).


2. S. Mukherjee, L. V. Hooper, Immunity 42 , 28 (2015).


3. Z. Hu et al., Science 374 , eabe6723 (2021).


4. A. Rapin, N. L. Harris, Trends Immunol. 39 , 724 (2018).


5. E. C. White et al., S c i. A d v. 4 , aap7399 (2018).


6. M. M. Zaiss et al., Immunity 43 , 998 (2015).


7. D. Ramanan et al., Science 352 , 608 (2016).


8. E. Candi, R. Schmidt, G. Melino, Nat. Rev. Mol. Cell Biol. 6 ,
   328 (2005).


9. K. A. Kline, A. L. Lewis, Microbiol. Spectr. 4 , UTI-0012
   (2021).

ACKNOWLEDGMENTS

N.L.H. is supported by a National Health and Medical

Research Council (NHMRC) of Australia SRF-B fellowship.

10.1126/science.abm3876

Gram-positive bacterial infection

Pathogen

invasion

Microbiota

dissemination

Helminth infection

No SPRR2A expression

Intestinal

lumen

Mucous

layer

Commensal

bacteria

Listeria

monocytogenes

Goblet

cells

Paneth

cells

I L- 4

I L-13

PPP

cececece

Helminth

An antimicrobial protein with dual roles

Paneth cells and goblet cells in the host intestinal epithelium secrete small proline-rich protein 2A (SPRR2A)

to prevent luminal bacteria from invading tissue during homeostasis and helminth infection. SPRR2A

production is promoted by pathogenic bacterial colonization or by interleukin-4 (IL-4) and/or IL-13 production.

When SPRR2A is absent, bacteria invade intestinal tissue during Gram-positive bacterial infection and

helminth infection, causing inflammation.

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