In­di­vid­u­als who suf­fer a stroke are in the high-risk group for a se­vere course of Covid-19 disease.

That is be­cause the bind­ing to ACE2 is me­di­at­ed via the spike gly­co­pro­tein present on the vi­ral sur­face. Re­cent clin­i­cal da­ta have demon­strat­ed that pa­tients with pre­vi­ous episodes of brain in­juries are a high-risk group for SARS-CoV-2 in­fec­tion. An ex­pla­na­tion for this find­ing is cur­rent­ly lack­ing. Ster­ile tis­sue in­juries in­clud­ing stroke in­duce the re­lease of sev­er­al in­flam­ma­to­ry me­di­a­tors that might mod­u­late the ex­pres­sion lev­els of sig­nal­ing pro­teins in dis­tant or­gans. Whether sys­temic in­flam­ma­tion fol­low­ing brain in­jury can specif­i­cal­ly mod­u­late ACE2 ex­pres­sion in dif­fer­ent vi­tal tis­sues has not been investigated.

An­giotensin-con­vert­ing en­zyme (ACE) 2 is present in mam­malian tis­sues and plays an im­por­tant role in the res­o­lu­tion of in­flam­ma­tion and cel­lu­lar home­osta­sis un­der in­flam­ma­to­ry con­di­tions. The stim­u­la­tion of ACE2 with spe­cif­ic ac­ti­va­tors is pro­tec­tive in spe­cif­ic dis­eases, such as brain in­jury in­duced by an is­chemic stroke. How­ev­er, re­cent da­ta have demon­strat­ed that SARS-CoV-2, the coro­n­avirus caus­ing COVID-19, uti­lizes ACE2 for en­ter­ing in­to the ep­ithe­lial cells. The en­su­ing in­fec­tion is ac­com­pa­nied by in­flam­ma­to­ry lung in­jury and death and has caused a world­wide epi­dem­ic since its start at the end of 2019. Al­though the lungs are the ma­jor tar­get of the virus, its spread to the heart, kid­ney, and brain has al­so been ob­served in hu­man pa­tients. This mul­ti-or­gan tar­get of the virus in­fec­tion has been as­so­ci­at­ed with the dys­func­tion of af­fect­ed or­gans and poor survival.

Stroke-in­duced im­mune ac­ti­va­tion can af­fect mul­ti­ple vi­tal or­gans and aug­ment the pro­gres­sion of spe­cif­ic co-ex­ist­ing in­flam­ma­to­ry dis­eases. Pre­vi­ous find­ings have shown that the in­duc­tion of stroke in murine mod­els of brain is­chemia can ac­ti­vate im­mune cells and pro­mote the pro­gres­sion of in­flam­ma­to­ry heart dis­ease. More­over, brain in­jury can mod­u­late the func­tions of the in­tes­tine and its im­mune com­po­nents, sup­port­ing the hy­poth­e­sis of mul­ti-or­gan fail­ure af­ter stroke. In ad­di­tion, stroke pa­tients may present signs of se­vere im­muno­sup­pres­sion and in­flam­ma­tion that of­ten lead to hos­pi­tal-ac­quired res­pi­ra­to­ry in­fec­tions. A re­cent study by Austin et al. has demon­strat­ed an in­creased num­ber of mononu­clear gran­u­lo­cytes in bron­choalve­o­lar lavage flu­id (BAL) and high­er IL-1β ex­pres­sion in lung tis­sue of mice that were sub­ject­ed to is­chemia-in­duced brain in­jury. In this re­spect, it is high­ly con­spic­u­ous that re­cent stud­ies have sug­gest­ed that pa­tients with car­dio­vas­cu­lar dis­eases and stroke form a high-risk group for SARS-CoV-2 in­fec­tion. Be­sides, there are a pletho­ra of clin­i­cal stud­ies that iden­ti­fied se­vere episodes of stroke in COVID-19 pa­tients. How­ev­er, whether post-stroke im­mune al­ter­ations and lung in­flam­ma­tion might in­crease the sus­cep­ti­bil­i­ty of pa­tients to SARS-CoV-2 in­fec­tion is cur­rent­ly enig­mat­ic and re­quires care­ful examination.

Hence, we hy­poth­e­sized that brain in­jury-in­duced im­muno­log­i­cal al­ter­ations and sys­temic in­flam­ma­to­ry con­di­tions may mod­u­late the ex­pres­sion of ACE2 in dif­fer­ent vi­tal or­gans and there­by, pro­mote bind­ing and in­fec­tion of SARS-CoV-2. At present, there is no da­ta avail­able demon­strat­ing the dy­nam­ics of mem­brane-bound and sol­u­ble ACE2 in murine tis­sues af­ter ster­ile brain in­jury. Here, us­ing an ex­per­i­men­tal murine mod­el of stroke we found that fo­cal cere­bral is­chemia specif­i­cal­ly in­creased the ex­pres­sion of ACE2 in the lungs but not in oth­er vi­tal organs.